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Sample records for suppressed locomotor activity

  1. Panic disorder and locomotor activity

    Science.gov (United States)

    Sakamoto, Noriyuki; Yoshiuchi, Kazuhiro; Kikuchi, Hiroe; Takimoto, Yoshiyuki; Kaiya, Hisanobu; Kumano, Hiroaki; Yamamoto, Yoshiharu; Akabayashi, Akira

    2008-01-01

    Background Panic disorder is one of the anxiety disorders, and anxiety is associated with some locomotor activity changes such as "restlessness". However, there have been few studies on locomotor activity in panic disorder using actigraphy, although many studies on other psychiatric disorders have been reported using actigraphy. Therefore, the aim of the present study was to investigate the relationship between panic disorder and locomotor activity pattern using a wrist-worn activity monitor. In addition, an ecological momentary assessment technique was used to record panic attacks in natural settings. Methods Sixteen patients with panic disorder were asked to wear a watch-type computer as an electronic diary for recording panic attacks for two weeks. In addition, locomotor activity was measured and recorded continuously in an accelerometer equipped in the watch-type computer. Locomotor activity data were analyzed using double cosinor analysis to calculate mesor and the amplitude and acrophase of each of the circadian rhythm and 12-hour harmonic component. Correlations between panic disorder symptoms and locomotor activity were investigated. Results There were significant positive correlations between the frequency of panic attacks and mesor calculated from double cosinor analysis of locomotor activity (r = 0.55) and between HAM-A scores and mesor calculated from double cosinor analysis of locomotor activity (r = 0.62). Conclusion Panic disorder patients with more panic attacks and more anxiety have greater objectively assessed locomotor activity, which may reflect the "restlessness" of anxiety disorders. PMID:19017383

  2. Suppression of Locomotor Activity in Female C57Bl/6J Mice Treated with Interleukin-1β: Investigating a Method for the Study of Fatigue in Laboratory Animals.

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    David R Bonsall

    Full Text Available Fatigue is a disabling symptom in patients with multiple sclerosis and Parkinson's Disease, and is also common in patients with traumatic brain injury, cancer, and inflammatory disorders. Little is known about the neurobiology of fatigue, in part due to the lack of an approach to induce fatigue in laboratory animals. Fatigue is a common response to systemic challenge by pathogens, a response in part mediated through action of the pro-inflammatory cytokine interleukin-1 beta (IL-1β. We investigated the behavioral responses of mice to IL-1β. Female C57Bl/6J mice of 3 ages were administered IL-1β at various doses i.p. Interleukin-1β reduced locomotor activity, and sensitivity increased with age. Further experiments were conducted with middle-aged females. Centrally administered IL-1β dose-dependently reduced locomotor activity. Using doses of IL-1β that caused suppression of locomotor activity, we measured minimal signs of sickness, such as hyperthermia, pain or anhedonia (as measured with abdominal temperature probes, pre-treatment with the analgesic buprenorphine and through sucrose preference, respectively, all of which are responses commonly reported with higher doses. We found that middle-aged orexin-/- mice showed equivalent effects of IL-1β on locomotor activity as seen in wild-type controls, suggesting that orexins are not necessary for IL-1β -induced reductions in wheel-running. Given that the availability and success of therapeutic treatments for fatigue is currently limited, we examined the effectiveness of two potential clinical treatments, modafinil and methylphenidate. We found that these treatments were variably successful in restoring locomotor activity after IL-1β administration. This provides one step toward development of a satisfactory animal model of the multidimensional experience of fatigue, a model that could allow us to determine possible pathways through which inflammation induces fatigue, and could lead to novel

  3. Clozapine-Induced Locomotor Suppression is Mediated by 5-HT2A Receptors in the Forebrain

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    McOmish, Caitlin E; Lira, Alena; Hanks, James B; Gingrich, Jay A

    2012-01-01

    The need for safer, more effective therapeutics for the treatment of schizophrenia is widely acknowledged. To optimally target novel pharmacotherapies, in addition to establishing the mechanisms responsible for the beneficial effects of antipsychotics, the pathways underlying the most severe side effects must also be elucidated. Here we investigate the role of serotonin 2A (5-HT2A), serotonin 2C (5-HT2C), and dopamine 2 receptors (D2) in mediating adverse effects associated with canonical first- and second-generation antipsychotic drugs in mice. Wild-type (WT) and 5-HT2A knockout (KO) mice treated with haloperidol, clozapine, and risperidone were assessed for locomotor activity and catalepsy. WT mice showed a marked reduction in locomotor activity following acute administration of haloperidol and high-dose risperidone, which was most likely secondary to the severe catalepsy caused by these compounds. Clozapine also dramatically reduced locomotor activity, but in the absence of catalepsy. Interestingly, 5-HT2A KO mice were cataleptic following haloperidol and risperidone, but did not respond to clozapine's locomotor-suppressing effects. Restoration of 5-HT2A expression to cortical glutamatergic neurons re-instated the locomotor-suppressing effects of clozapine in the open field. In sum, we confirm that haloperidol and risperidone caused catalepsy in rodents, driven by strong antagonism of D2. We also demonstrate that clozapine decreases locomotor activity in a 5-HT2A-dependent manner, in the absence of catalepsy. Moreover, we show that it is the cortical population of 5-HT2A that mediate the locomotor-suppressing effects of clozapine. PMID:22871913

  4. Sensory-evoked perturbations of locomotor activity by sparse sensory input: a computational study

    OpenAIRE

    Bui, Tuan V.; Brownstone, Robert M.

    2015-01-01

    Sensory inputs from muscle, cutaneous, and joint afferents project to the spinal cord, where they are able to affect ongoing locomotor activity. Activation of sensory input can initiate or prolong bouts of locomotor activity depending on the identity of the sensory afferent activated and the timing of the activation within the locomotor cycle. However, the mechanisms by which afferent activity modifies locomotor rhythm and the distribution of sensory afferents to the spinal locomotor networks...

  5. Melatonin reduces locomotor activity and circulating cortisol in goldfish.

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    Azpeleta, Clara; Martínez-Alvarez, Rosa María; Delgado, María Jesús; Isorna, Esther; De Pedro, Nuria

    2010-03-01

    The present study focused on the effects of a subchronic melatonin treatment on locomotor activity and cortisol plasma levels in goldfish. We compared two different administration routes: peripheral (10 microg/g body weight) versus central (1 microg/microl) injections of melatonin for 7 or 4 days, respectively. Daily locomotor activity, including both diurnal and nocturnal activities, food anticipatory activity and circulating cortisol at 11:00 (under 24 h of food deprivation and 17 h postinjection) were significantly reduced after repeated intraperitoneal injections with melatonin for 7 days, but not after intracerebroventricular treatment. Taking in mind the anoretic effect of melatonin in this species, we investigated if such feeding reduction is directly responsible for the reduction in motor activity induced by melatonin treatment. Food restriction (50%) for 10 days did not significantly modify either daily locomotor activity or plasma cortisol levels in goldfish, indicating that the peripheral action of melatonin diminishing locomotor activity in goldfish is not a direct consequence of its anoretic action. In summary, our results indicate that, as previously described in other vertebrate species, melatonin can regulate locomotor activity and cortisol levels in goldfish, suggesting a sedative effect of this hormone in this teleost. Copyright 2010 Elsevier Inc. All rights reserved.

  6. Olanzapine affects locomotor activity and meal size in male rats

    NARCIS (Netherlands)

    van der Zwaal, Esther M.; Luijendijk, Mieneke C. M.; Evers, Simon S.; la Fleur, Susanne E.; Adan, Roger A. H.

    2010-01-01

    Olanzapine is an antipsychotic drug that frequently induces weight gain accompanied by increased fat deposition as a side effect To investigate how olanzapine affects different aspects of energy balance we used male rats to determine effects on meal patterns food preference locomotor activity and

  7. Olanzapine affects locomotor activity and meal size in male rats

    NARCIS (Netherlands)

    van der Zwaal, Esther M.; Luijendijk, Mieneke C. M.; Evers, Simon S.; la Fleur, Susanne E.; Adan, Roger A. H.

    2010-01-01

    Olanzapine is an antipsychotic drug that frequently induces weight gain accompanied by increased fat deposition as a side effect. To investigate how olanzapine affects different aspects of energy balance, we used male rats to determine effects on meal patterns, food preference, locomotor activity

  8. Effects of nutmeg consumption on the open field locomotor activities ...

    African Journals Online (AJOL)

    ... was a steady significant difference (p < 0.05) in the behaviours of line crossing and walling. There was no much significant changes (P<0.05) in the behaviours of hinding, grooming and defeacation between the Treatments and Control groups of animals. Keywords: Nutmeg, Wistar rats, Open field, Locomotor activities ...

  9. Hesperidin effects on behavior and locomotor activity of diabetic ...

    African Journals Online (AJOL)

    Tuoyo Aghomotsegin

    2016-11-09

    Nov 9, 2016 ... after treatment of Ruta graveolens and rutin with nicotinamide/streptozotocin diabetic rats (Gispen and. Biessels, 2000). After treating with hesperidin, there was an increase in the anxiety level which improved locomotor activity and recovery time during testing in open field. The same remark was made for ...

  10. Inbreeding affects locomotor activity in Drosophila melanogaster at different ages

    DEFF Research Database (Denmark)

    Manenti, Tommaso; Pertoldi, Cino; Nasiri Moghadam, Neda

    2015-01-01

    The ability to move is essential for many behavioural traits closely related to fitness. Here we studied the effect of inbreeding on locomotor activity (LA) of Drosophila melanogaster at different ages under both dark and light regimes. We expected to find a decreased LA in inbred lines compared...

  11. Locomotor activity of professional football referees

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    Y.V. Manilo

    2014-12-01

    Full Text Available Purpose : To study the structure of the motor activity of foreign (European football referees qualifications and Ukrainian arbitrators (Premier League, the first, second league. The objectives of the study was to determine the amount and direction of the motor activity of soccer referees. Also perform a comparative analysis of the motor activity of football referees of different qualifications in Europe and Ukraine. Material : The study involved 38 referees - soccer referees first, second, of the Premier League with the different regions of Ukraine, as well as foreign arbitrators FIFA. Results : It was found that in the period of the motor activity of the arbitrator was walking - 13.0% of the total distance when moving, running at a moderate pace - 67.4%, accelerating - 16.7%, jumps - 2.9%. Average per match referee overcomes distance 8970.2 m: foreign arbitrators - 12,030.0 m., Arbitrators Premier League - 9292.5 m., 1 league - 7530.0 m., 2 leagues - 7028.3 m. Ukrainian Premier League referees are inferior to move moderate jogging foreign arbitrators FIFA respectively - 6,425.0 m (69.1% and 9615.3 m (79.9%. Conclusions : The results of the research showed that the magnitude of motor activity during football matches in professional arbitrators may be different. It depends on their physical fitness Championship (competition, the league, the level of the teams playing, the nature of the intensity of the match. The arbitrator must remain near the gaming moments to control them and prevent possible confrontation.

  12. Sensory-evoked perturbations of locomotor activity by sparse sensory input: a computational study.

    Science.gov (United States)

    Bui, Tuan V; Brownstone, Robert M

    2015-04-01

    Sensory inputs from muscle, cutaneous, and joint afferents project to the spinal cord, where they are able to affect ongoing locomotor activity. Activation of sensory input can initiate or prolong bouts of locomotor activity depending on the identity of the sensory afferent activated and the timing of the activation within the locomotor cycle. However, the mechanisms by which afferent activity modifies locomotor rhythm and the distribution of sensory afferents to the spinal locomotor networks have not been determined. Considering the many sources of sensory inputs to the spinal cord, determining this distribution would provide insights into how sensory inputs are integrated to adjust ongoing locomotor activity. We asked whether a sparsely distributed set of sensory inputs could modify ongoing locomotor activity. To address this question, several computational models of locomotor central pattern generators (CPGs) that were mechanistically diverse and generated locomotor-like rhythmic activity were developed. We show that sensory inputs restricted to a small subset of the network neurons can perturb locomotor activity in the same manner as seen experimentally. Furthermore, we show that an architecture with sparse sensory input improves the capacity to gate sensory information by selectively modulating sensory channels. These data demonstrate that sensory input to rhythm-generating networks need not be extensively distributed. Copyright © 2015 the American Physiological Society.

  13. Daily rhythms of locomotor and demand-feeding activities in Schizothorax pelzami (Kessler, 1870).

    Science.gov (United States)

    Ebrahimi, Ehsan; Kamrani, Ehsan; Heydarnejad, Mohammad Saeed; Safari, Omid

    2017-01-01

    A study was carried out to investigate the daily rhythms of locomotor and feeding activity of Khajoo, Schizothorax pelzami, a candidate species for freshwater aquaculture. Using self-feeder juvenile Khajoo were exposed to a 12/12 LD cycle to determine the rhythms of locomotor and feeding activity. The effects of feeding on locomotor and feeding activity of fish were also examined. Finally, the endogenous rhythmicity under different lighting condition tested. Fish displayed a strictly diurnal feeding and locomotor activities with 98% and 84% of the total activity occurred in the photophase, respectively. In scheduled feeding, both the L-group (fed in light) and the D-group (fed in the dark) showed a diurnal locomotor activity pattern. However, the L-group had a peak of locomotor activity near the feeding time, but the D-group had a scarce locomotor activity in the scatophase with no significant change at the mealtime. Most of the individuals display free-running rhythms when exposed to different lighting condition including, constant darkness, ultradian 45:45 min LD cycle and reversed DL photo cycle. Taken together the results of this study showed that both locomotor and feeding activity have diurnal rhythms in Khajoo S. pelzami, even fish feeding had taken place at night. Additionally, the free-running locomotor activity of the fish in the absence of external light stimuli, suggests the existence of an endogenous timing mechanism in this fish species.

  14. Dopamine receptors modulate ethanol's locomotor-activating effects in preweanling rats

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    Arias, Carlos; Mlewski, Estela C.; Hansen, Cristian; Molina, Juan Carlos; Paglini, Maria Gabriela; Spear, Norman E.

    2011-01-01

    Near the end of the second postnatal week motor activity is increased soon after ethanol administration (2.5 g/kg) while sedation-like effects prevail when blood ethanol levels reach peak values. This time course coincides with biphasic reinforcement (appetitive and aversive) effects of ethanol determined at the same age. The present experiments tested the hypothesis that ethanol-induced activity during early development in the rat depends on the dopamine system, which is functional in modulating motor activity early in ontogeny. Experiments 1a and 1b tested ethanol-induced activity (0 or 2.5 g/kg) after a D1-like (SCH23390; 0, 0.015, 0.030 or 0.060 mg/kg) or a D2-like (sulpiride; 0, 5, 10 or 20 mg/kg) receptor antagonist, respectively. Ethanol-induced stimulation was suppressed by SCH23390 or sulpiride. The dopaminergic antagonists had no effect on blood ethanol concentration (Experiments 2a and 2b). In Experiment 3, 2.5 g/kg ethanol increased dopamine concentration in striatal tissue as well as locomotor activity in infant Wistar rats. Adding to our previous results showing a reduction in ethanol induced activity by a GABA B agonist or a nonspecific opioid antagonist, the present experiments implicate both D1-like and D2-like dopamine receptors in ethanol-induced locomotor stimulation during early development. According to these results, the same mechanims that modulate ethanol-mediated locomotor stimulation in adult rodents seem to regulate this particular ethanol effect in the infant rat. PMID:19842128

  15. [The locomotor activity of the squirrel (Sciurus vulgaris)].

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    Zwahlen, R

    1975-03-01

    The locomotor activity of Sciurus vulgaris has been observed in the field and in caged animals.Onset and cessation of activity (data from the cage only): Activity starts before sunrise and correlation with sunrise is very high (0.838≤r≤0.990). Cessation of activity normally lies before sunset, during summer late in the afternoon, in winter often already before noon. It is scatterd to a greater extent than onset of activity, correlation with sunset being 0.535≤r ≤0.798.Daily pattern: It is a bigeminus, although widely subject to seasonal variations. The afternoon peak is lacking from November till February, begins to form in March and reaches as much as 33.5% of total activity in September. The pause occurring at noon is most distinct during summer and vanishes gradually during the autumn months. Data from the field and from the cage show essentially the same pattern.Annual pattern: In the cage, activity is least during winter, increases gradually to a maximum in September followed by a sharp decrease to the winter minimum. The curve derived from the field observations shows a bimodal shape with a first peak in April and a second, more distinct one in September. A combination of the two groups of data shows three phases: December to May with irregular variations, May to September showing a conspicuous increase to maximal activity, September to December with sharp decrease to the winter minimum.

  16. Adaptive locomotor network activation during randomized walking speeds using functional near-infrared spectroscopy.

    Science.gov (United States)

    Kim, Ha Yeon; Kim, Eun Joo; You, Joshua Sung H

    2017-07-20

    An improved understanding of the mechanisms underlying locomotor networks has the potential to benefit the neurorehabilitation of patients with neurological locomotor deficits. However, the specific locomotor networks that mediate adaptive locomotor performance and changes in gait speed remain unknown. The aim of the present study was to examine patterns of cortical activation associated with the walking speeds of 1.5, 2.0, 2.5, and 3.0 km/h on a treadmill. Functional near-infrared spectroscopy (fNIRS) was performed on a 30-year-old right-handed healthy female subject, and cerebral hemodynamic changes were observed in cortical locomotor network areas including the primary sensorimotor cortex (SMC), premotor cortex (PMC), supplementary motor area (SMA), prefrontal cortex (PFC), and sensory association cortex (SAC). The software package NIRS-statistical parametric mapping (NIRS-SPM) was utilized to analyze fNIRS data in the MATLAB environment. SPM t-statistic maps were computed at an uncorrected threshold of pglobalized locomotor network activation of the SMC, PMC, SMA, and PMC; additionally, the site with the highest cortical activation ratio shifted from the SMC to the SMA. Global locomotor network recruitment, in particular PFC activation indicated by OxyHb in our study, may indicate a response to increased cognitive-locomotor demand due to simultaneous postural maintenance and leg movement coordination.

  17. Effect of physical activity and 217-Hz extremely low frequency electromagnetic field on rat locomotor activity

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    Rasol Zeidabadi

    2017-02-01

    Full Text Available Background: Nowadays the widespread use of cell phones has increased concerns about the biological effects of electromagnetic fields on human body. The purpose of the present study was to examine the role of physical activity in moderating the effects of extremely low frequency electromagnetic fields (ELF-EMF emitted from cell phones on rat locomotor activity. Material and Methods: Male Albino-Wistar rats (no=70 were divided into seven groups: Short and Long- term physical activity; Control, ELF-EMF; Sham; Long-term physical activity+ELF-EMF; Short-term physical activity+ELF-EMF. Short and Long- term physical activity groups were forced to daily treadmill running (30 minutes for one week and one month, respectively. ELF-EMF group was exposed to ELF-EMF cell phone simulator for three hours during the period. Having placed in the ELF-EMF simulator device, the physical activity+ELF-EMF groups were transferred to treadmill. Locomotor activity were analyzed as distance, time and speed of movement in open field apparatus. Results: The results showed that the ELF-EMF from cell phones can significantly decrease the locomotor activity in the exposed rats. On the other hand, short and long-term physical activity significantly increased motor activity in the trained rats (P≤0.05. However, there was no significant difference between the combination groups (Physical activity+ELF-EMF and ELF group in locomotor activity. Conclusion: The results revealed that the physical activity could not prevent the decrease of locomotor activity caused by ELF-EMF from cell phone.

  18. Involvement of nigral oxytocin in locomotor activity: A behavioral, immunohistochemical and lesion study in male rats.

    Science.gov (United States)

    Angioni, Laura; Cocco, Cristina; Ferri, Gian-Luca; Argiolas, Antonio; Melis, Maria Rosaria; Sanna, Fabrizio

    2016-07-01

    Oxytocin is involved in the control of different behaviors, from sexual behavior and food consumption to empathy, social and affective behaviors. An imbalance of central oxytocinergic neurotransmission has been also associated with different mental pathologies, from depression, anxiety and anorexia/bulimia to schizophrenia, autism and drug dependence. This study shows that oxytocin may also play a role in the control of locomotor activity. Accordingly, intraperitoneal oxytocin (0.5-2000μg/kg) reduced locomotor activity of adult male rats. This effect was abolished by d(CH2)5Tyr(Me)(2)-Orn(8)-vasotocin, an oxytocin receptor antagonist, given into the lateral ventricles at the dose of 2μg/rat, which was ineffective on locomotor activity. Oxytocin (50-200ng/site) also reduced and d(CH2)5Tyr(Me)(2)-Orn(8)-vasotocin (2μg/site) increased locomotor activity when injected bilaterally into the substantia nigra, a key area in the control of locomotor activity. Conversely, the destruction of nigral neurons bearing oxytocin receptors by the recently characterized neurotoxin oxytocin-saporin injected into the substantia nigra, increased basal locomotor activity. Since oxytocin-saporin injected into the substantia nigra caused a marked reduction of neurons immunoreactive for tyrosine hydroxylase (e.g., nigrostriatal dopaminergic neurons) and for vesicular glutamate transporters VGluT1, VGluT2 and VGluT3 (e.g., glutamatergic neurons), but not for glutamic acid decarboxylase (e.g., GABAergic neurons), together these findings suggest that oxytocin influences locomotor activity by acting on receptors localized presynaptically in nigral glutamatergic nerve terminals (which control the activity of nigral GABAergic efferent neurons projecting to brain stem nuclei controlling locomotor activity), rather than on receptors localized in the cell bodies/dendrites of nigrostriatal dopaminergic neurons. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  19. Oxytocin decreases cocaine taking, cocaine seeking, and locomotor activity in female rats.

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    Leong, Kah-Chung; Zhou, Luyi; Ghee, Shannon M; See, Ronald E; Reichel, Carmela M

    2016-02-01

    Oxytocin has been shown to decrease cocaine taking and seeking in male rats, suggesting potential treatment efficacy for drug addiction. In the present study, we extended these findings to the assessment of cocaine seeking and taking in female rats. Further, we made direct comparisons of oxytocin's impact on cocaine induced locomotor activity in both males and females. In females, systemic oxytocin (0.3, 1.0, 3.0 mg/kg) attenuated lever pressing for cocaine during self-administration and oxytocin (1.0 mg/kg) attenuated cue-induced cocaine seeking following extinction. Cocaine increased baseline locomotor activity to a greater degree in females relative to males. Oxytocin (0.1, 0.3, 1.0, and 3.0 mg/kg) reduced cocaine-induced locomotor activity in females, but not significantly in males. These data illustrate sex similarities in oxytocin's attenuation of cocaine seeking, but sex differences in cocaine-induced locomotor effects. While reductions in cocaine seeking cannot be attributed to a reduction in locomotor activity in males, attenuation of locomotor function cannot be entirely ruled out as an explanation for a decrease in cocaine seeking in females suggesting that oxytocin's effect on cocaine seeking may be mediated by different mechanisms in male and females. PsycINFO Database Record (c) 2016 APA, all rights reserved.

  20. Enhanced persistency of resting and active periods of locomotor activity in schizophrenia.

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    Wataru Sano

    Full Text Available Patients with schizophrenia frequently exhibit behavioral abnormalities associated with its pathological symptoms. Therefore, a quantitative evaluation of behavioral dynamics could contribute to objective diagnoses of schizophrenia. However, such an approach has not been fully established because of the absence of quantitative biobehavioral measures. Recently, we studied the dynamical properties of locomotor activity, specifically how resting and active periods are interwoven in daily life. We discovered universal statistical laws ("behavioral organization" and their alterations in patients with major depressive disorder. In this study, we evaluated behavioral organization of schizophrenic patients (n = 19 and healthy subjects (n = 11 using locomotor activity data, acquired by actigraphy, to investigate whether the laws could provide objective and quantitative measures for a possible diagnosis and assessment of symptoms. Specifically, we evaluated the cumulative distributions of resting and active periods, defined as the periods with physical activity counts successively below and above a predefined threshold, respectively. Here we report alterations in the laws governing resting and active periods; resting periods obeyed a power-law cumulative distribution with significantly lower parameter values (power-law scaling exponents, whereas active periods followed a stretched exponential distribution with significantly lower parameter values (stretching exponents, in patients. Our findings indicate enhanced persistency of both lower and higher locomotor activity periods in patients with schizophrenia, probably reflecting schizophrenic pathophysiology.

  1. Activity of Renshaw cells during locomotor-like rhythmic activity in the isolated spinal cord of neonatal mice

    DEFF Research Database (Denmark)

    Nishimaru, Hiroshi; Restrepo, Carlos E.; Kiehn, Ole

    2006-01-01

    % of the recorded RCs fired in-phase with the ipsilateral L2 flexor-related rhythm, whereas the rest fired in the extensor phase. Each population of RCs fired throughout the corresponding locomotor phase. All RCs received both excitatory and inhibitory synaptic inputs during the locomotor-like rhythmic activity...

  2. Cocaine locomotor activation, sensitization and place preference in six inbred strains of mice

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    Grabowski-Boase Laura

    2011-08-01

    Full Text Available Abstract Background The expanding set of genomics tools available for inbred mouse strains has renewed interest in phenotyping larger sets of strains. The present study aims to explore phenotypic variability among six commonly-used inbred mouse strains to both the rewarding and locomotor stimulating effects of cocaine in a place conditioning task, including several strains or substrains that have not yet been characterized for some or all of these behaviors. Methods C57BL/6J (B6, BALB/cJ (BALB, C3H/HeJ (C3H, DBA/2J (D2, FVB/NJ (FVB and 129S1/SvImJ (129 mice were tested for conditioned place preference to 20 mg/kg cocaine. Results Place preference was observed in most strains with the exception of D2 and 129. All strains showed a marked increase in locomotor activity in response to cocaine. In BALB mice, however, locomotor activation was context-dependent. Locomotor sensitization to repeated exposure to cocaine was most significant in 129 and D2 mice but was absent in FVB mice. Conclusions Genetic correlations suggest that no significant correlation between conditioned place preference, acute locomotor activation, and locomotor sensitization exists among these strains indicating that separate mechanisms underlie the psychomotor and rewarding effects of cocaine.

  3. Hepatic mTORC1 controls locomotor activity, body temperature, and lipid metabolism through FGF21

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    Cornu, Marion; Oppliger, Wolfgang; Albert, Verena; Robitaille, Aaron M.; Trapani, Francesca; Quagliata, Luca; Fuhrer, Tobias; Sauer, Uwe; Terracciano, Luigi; Hall, Michael N.

    2014-01-01

    The liver is a key metabolic organ that controls whole-body physiology in response to nutrient availability. Mammalian target of rapamycin (mTOR) is a nutrient-activated kinase and central controller of growth and metabolism that is negatively regulated by the tumor suppressor tuberous sclerosis complex 1 (TSC1). To investigate the role of hepatic mTOR complex 1 (mTORC1) in whole-body physiology, we generated liver-specific Tsc1 (L-Tsc1 KO) knockout mice. L-Tsc1 KO mice displayed reduced locomotor activity, body temperature, and hepatic triglyceride content in a rapamycin-sensitive manner. Ectopic activation of mTORC1 also caused depletion of hepatic and plasma glutamine, leading to peroxisome proliferator–activated receptor γ coactivator-1α (PGC-1α)–dependent fibroblast growth factor 21 (FGF21) expression in the liver. Injection of glutamine or knockdown of PGC-1α or FGF21 in the liver suppressed the behavioral and metabolic defects due to mTORC1 activation. Thus, mTORC1 in the liver controls whole-body physiology through PGC-1α and FGF21. Finally, mTORC1 signaling correlated with FGF21 expression in human liver tumors, suggesting that treatment of glutamine-addicted cancers with mTOR inhibitors might have beneficial effects at both the tumor and whole-body level. PMID:25082895

  4. Aging reveals a role for nigral tyrosine hydroxylase ser31 phosphorylation in locomotor activity generation.

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    Michael F Salvatore

    Full Text Available BACKGROUND: Tyrosine hydroxylase (TH regulates dopamine (DA bioavailability. Its product, L-DOPA, is an established treatment for Parkinson's disease (PD, suggesting that TH regulation influences locomotion. Site-specific phosphorylation of TH at ser31 and ser40 regulates activity. No direct evidence shows that ser40 phosphorylation is the dominating mechanism of regulating TH activity in vivo, and physiologically-relevant stimuli increase L-DOPA biosynthesis independent of ser40 phosphorylation. Significant loss of locomotor activity occurs in aging as in PD, despite less loss of striatal DA or TH in aging compared to the loss associated with symptomatic PD. However, in the substantia nigra (SN, there is equivalent loss of DA or TH in aging and at the onset of PD symptoms. Growth factors increase locomotor activity in both PD and aging models and increase DA bioavailability and ser31 TH phosphorylation in SN, suggesting that ser31 TH phosphorylation status in the SN, not striatum, regulates DA bioavailability necessary for locomotor activity. METHODOLOGY AND PRINCIPAL FINDINGS: We longitudinally characterized locomotor activity in young and older Brown-Norway Fischer 344 F(1 hybrid rats (18 months apart in age at two time periods, eight months apart. The aged group served as an intact and pharmacologically-naïve source of deficient locomotor activity. Following locomotor testing, we analyzed DA tissue content, TH protein, and TH phosphorylation in striatum, SN, nucleus accumbens, and VTA. Levels of TH protein combined with ser31 phosphorylation alone reflected inherent differences in DA levels among the four regions. Measures strictly pertaining to locomotor activity initiation significantly correlated to DA content only in the SN. Nigral TH protein and ser31 phosphorylation together significantly correlated to test subject's maximum movement number, horizontal activity, and duration. CONCLUSIONS/SIGNIFICANCE: Together, these results show ser

  5. Effect of thiamethoxam on cockroach locomotor activity is associated with its metabolite clothianidin.

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    Benzidane, Yassine; Touinsi, Sarra; Motte, Emilie; Jadas-Hécart, Alain; Communal, Pierre-Yves; Leduc, Lionel; Thany, Steeve H

    2010-12-01

    In the present study, the effect of thiamethoxam and clothianidin on the locomotor activity of American cockroach, Periplaneta americana (L.), was evaluated. Because it has been proposed that thiamethoxam is metabolised to clothianidin, high-performance liquid chromatography coupled with mass spectrometry was used to evaluate the amount of clothianidin on thiamethoxam-treated cockroaches. One hour after neonicotinoid treatment, the time spent in the open-field-like apparatus significantly increased, suggesting a decrease in locomotor activity. The percentage of cockroaches displaying locomotor activity was significantly reduced 1 h after haemolymph application of 1 nmol g(-1) neonicotinoid, while no significant effect was found after topical and oral administration. However, at 24 and 48 h, all neonicotinoids were able to reduce locomotor activity, depending on their concentrations and the way they were applied. Interestingly, it was found that thiamethoxam was converted to clothianidin 1 h after application, but the amount of clothianidin did not rise proportionately to thiamethoxam, especially after oral administration. The data suggest that the effect of thiamethoxam on cockroach locomotor activity is due in part to clothianidin action because (1) thiamethoxam levels remained persistent 48 h after application and (2) the amount of clothianidin in cockroach tissues was consistent with the toxicity of thiamethoxam. Copyright © 2010 Society of Chemical Industry.

  6. The effects of sex-ratio and density on locomotor activity in the house fly, Musca domestica

    DEFF Research Database (Denmark)

    Bahrndorff, Simon; Kjaersgaard, Anders; Pertoldi, Cino

    2012-01-01

    Although locomotor activity is involved in almost all behavioral traits, there is a lack of knowledge on what factors affect it. This study examined the effects of sex-ratio and density on the circadian rhythm of locomotor activity of adult Musca domestica L. (Diptera: Muscidae) using an infra...... with and without the presence of females. Overall, this study demonstrates that locomotor activity in M. domestica is affected by sex-ratio and density. Furthermore, the predictability of locomotor activity is affected by both sex-ratio, density, and circadian rhythm. These results add to our understanding...

  7. Comparison of caffeine-induced locomotor activity between adolescent and adult rats.

    Science.gov (United States)

    Marin, Marcelo T; Zancheta, Roberta; Paro, Ana H; Possi, Ana P M; Cruz, Fábio C; Planeta, Cleopatra S

    2011-06-25

    Caffeine is the psychostimulant drug most consumed in the world. This drug is present in food, beverages and medicines marketed for individuals of all ages. In spite of this, caffeine effects on adolescents are poorly understood. The aim of this study was to evaluate the differences on caffeine-induced locomotor stimulant or depressant effects in adolescent and adult rats. Adolescent (37-40 days old) or adult (70-74 days old) Wistar rats were tested for stimulant and depressant caffeine effects in two different experiments. The first was designed to evaluate the locomotor effect of caffeine in habituated rats. To this end, rats were previously habituated to test environment and had their locomotor activity registered following i.p. injections of vehicle or caffeine (3, 10, 30, 60 or 120 mg/kg). In the second experiment adolescent or adult rats were not habituated to the test environment and their locomotor activity was registered following i.p. injections of vehicle or caffeine (30, 60 or 120 mg/kg). In both experiments caffeine-induced a biphasic effect, with stimulation in small to moderate drug doses and no effect or locomotor depression in higher caffeine doses. Moreover, caffeine-induced locomotor stimulation was higher in adolescent than adult rats. Also, locomotor depression was only revealed in adult rats non-habituated to the test environment. These results suggest that adult and adolescent respond differently to caffeine indicating the need of more studies on the effects of caffeine in animals' models of adolescence. Copyright © 2011 Elsevier B.V. All rights reserved.

  8. Effects of sex pheromones and sexual maturation on locomotor activity in female sea lamprey (Petromyzon marinus)

    Science.gov (United States)

    Walaszczyk, Erin J.; Johnson, Nicholas S.; Steibel, Juan Pedro; Li, Weiming

    2013-01-01

    Synchronization of male and female locomotor rhythmicity can play a vital role in ensuring reproductive success. Several physiological and environmental factors alter these locomotor rhythms. As sea lamprey, Petromyzon marinus, progress through their life cycle, their locomotor activity rhythm changes multiple times. The goal of this study was to elucidate the activity patterns of adult female sea lamprey during the sexual maturation process and discern the interactions of these patterns with exposure to male pheromones. During these stages, preovulated and ovulated adult females are exposed to sex pheromone compounds, which are released by spermiated males and attract ovulated females to the nest for spawning. The locomotor behavior of adult females was monitored in a natural stream with a passive integrated tag responder system as they matured, and they were exposed to a sex pheromone treatment (spermiated male washings) or a control (prespermiated male washings). Results showed that, dependent on the hour of day, male sex pheromone compounds reduce total activity (p rhythm in a vertebrate, and they suggest that the interaction between maturity stage and sex pheromone exposure contributes to the differential locomotor rhythms found in adult female sea lamprey. This phenomenon may contribute to the reproductive synchrony of mature adults, thus increasing reproductive success in this species.

  9. Efficacy of Static Magnetic Field for Locomotor Activity of Experimental Osteopenia

    Directory of Open Access Journals (Sweden)

    Norimasa Taniguchi

    2007-01-01

    Full Text Available In order to examine the effectiveness of applying a static magnetic field (SMF for increasing bone mineral density (BMD, we assessed the degree of osteopenia by dual-energy X-ray absorptiometry (DEXA, the metabolism measuring system, and histological examination of bone tissue in an ovariectomized (OVX rat model. Thirty-six female Wistar rats (8 weeks old, 160–180 g were divided into three groups. The rats in the OVX-M group were exposed to SMF for 12 weeks after ovariectomy. The ovariectomized rats in the OVX-D group were not exposed to SMF as a control. The rats in the normal group received neither ovariectomy nor exposure to SMF. Twelve-week exposure to SMF in the OVX-M group inhibited the reduction in BMD that was observed in the OVX-D group. Moreover, in the OVX rats, before exposure to SMF, there was no clear difference in the level of locomotor activity between the active and resting phases, and the pattern of locomotor activity was irregular. After exposure of OVX rats to SMF, the pattern of locomotor activity became diphasic with clear active and resting phases, as was observed in the normal group. In the OVX-M group, the continuity of the trabecular bone was maintained more favorably and bone mass was higher than the respective parameters in the OVX-D group. These results demonstrate that exposure to SMF increased the level of locomotor activity in OVX rats, thereby increasing BMD.

  10. Cocaine-induced locomotor activity in rats selectively bred for low and high voluntary running behavior.

    Science.gov (United States)

    Brown, Jacob D; Green, Caroline L; Arthur, Ian M; Booth, Frank W; Miller, Dennis K

    2015-02-01

    The rewarding effects of physical activity and abused drugs are caused by stimulation of similar brain pathways. Low (LVR) and high (HVR) voluntary running lines were developed by selectively breeding Wistar rats on running distance performance on postnatal days 28-34. We hypothesized that LVR rats would be more sensitive to the locomotor-activating effects of cocaine than HVR rats due to their lower motivation for wheel running. We investigated how selection for LVR or HVR behavior affects inherited activity responses: (a) open field activity levels, (b) habituation to an open field environment, and (c) the locomotor response to cocaine. Open field activity was measured for 80 min on three successive days (days 1-3). Data from the first 20 min were analyzed to determine novelty-induced locomotor activity (day 1) and the habituation to the environment (days 1-3). On day 3, rats were acclimated to the chamber for 20 min and then received saline or cocaine (10, 20, or 30 mg/kg) injection. Dopamine transporter (DAT) protein in the nucleus accumbens was measured via Western blot. Selecting for low and high voluntary running behavior co-selects for differences in inherent (HVR > LVR) and cocaine-induced (LVR > HVR) locomotor activity levels. The differences in the selected behavioral measures do not appear to correlate with DAT protein levels. LVR and HVR rats are an intriguing physical activity model for studying the interactions between genes related to the motivation to run, to use drugs of abuse, and to exhibit locomotor activity.

  11. Drugs that Target Dopamine Receptors: Changes in Locomotor Activity in Larval Zebrafish

    Science.gov (United States)

    As part of an effort at the US Environmental Protection Agency to develop a rapid in vivo screen for prioritization of toxic chemicals, we have begun to characterize the locomotor activity of zebrafish (Danio rerio) larvae. This includes assessing the acute effects of drugs known...

  12. [On mechanism of functional changes in the organism of teenagers at different levels of locomotor activity].

    Science.gov (United States)

    Mindubaeva, F A; Shukurov, F A; Salikhova, Y Y; Niyazova, Y I; Ramazanov, A K

    2015-02-01

    Comprehensive study of the cardiovascular system functional condition of 15-16 teenagers while in normal daily locomotor activity and in the mode of regular moderate physical activity was performed. The features of cerebral circulation and myocardium functional condition of teenagers are studied depending on initial tonus of the autonomic nervous system and locomotor activity level in the process of continuous step physical activity on tredmil. The condition of regulatory mechanisms, providing adaptation of teenagers in the conditions of modern school was studied. Research results showed, that elasticity of cerebrum arterial vessels, veins tone, venous outflow for teenagers not having regular physical activity, considerably mionectic. More adequate reaction of coronary blood flow in the process of physical activity is educed for the trained teenagers with the balanced autonomic regulation of cardiac rhythm. This group showed a higher level and regulation quality of organism reserve possibilities.

  13. Decrease of GSK3β phosphorylation in the rat nucleus accumbens core enhances cocaine-induced hyper-locomotor activity.

    Science.gov (United States)

    Kim, Wha Y; Jang, Ju K; Lee, Jung W; Jang, Hyunduk; Kim, Jeong-Hoon

    2013-06-01

    Glycogen synthase kinase 3β (GSK3β), which is abundantly present in the brain, is known to contribute to psychomotor stimulant-induced locomotor behaviors. However, most studies have been focused in showing that GSK3β is able to attenuate psychomotor stimulants-induced hyperactivity by increasing its phosphorylation levels in the nucleus accumbens (NAcc). So, here we examined in the opposite direction about the effects of decreased phosphorylation of GSK3β in the NAcc core on both basal and cocaine-induced locomotor activity by a bilateral microinjection into this site of an artificially synthesized peptide, S9 (0.5 or 5.0 μg/μL), which contains sequences around N-terminal serine 9 residue of GSK3β. We found that decreased levels of GSK3β phosphorylation in the NAcc core enhance cocaine-induced hyper-locomotor activity, while leaving basal locomotor activity unchanged. This is the first demonstration, to our knowledge, that the selective decrease of GSK3β phosphorylation levels in the NAcc core may contribute positively to cocaine-induced locomotor activity, while this is not sufficient for the generation of locomotor behavior by itself without cocaine. Taken together, these findings importantly suggest that GSK3β may need other molecular targets which are co-activated (or deactivated) by psychomotor stimulants like cocaine to contribute to generation of locomotor behaviors. © 2013 International Society for Neurochemistry.

  14. Influence of temperature on daily locomotor activity in the crab Uca pugilator.

    Directory of Open Access Journals (Sweden)

    Audrey M Mat

    Full Text Available Animals living in the intertidal zone are exposed to prominent temperature changes. To cope with the energetic demands of environmental thermal challenges, ectotherms rely mainly on behavioral responses, which may change depending on the time of the day and seasonally. Here, we analyze how temperature shapes crabs' behavior at 2 different times of the year and show that a transition from constant cold (13.5°C to constant warm (17.5°C water temperature leads to increased locomotor activity levels throughout the day in fiddler crabs (Uca pugilator collected during the summer. In contrast, the same transition in environmental temperature leads to a decrease in the amplitude of the daily locomotor activity rhythm in crabs collected during the winter. In other words, colder temperatures during the cold season favor a more prominent diurnal behavior. We interpret this winter-summer difference in the response of daily locomotor activity to temperature changes within the framework of the circadian thermoenergetics hypothesis, which predicts that a less favorable energetic balance would promote a more diurnal activity pattern. During the winter, when the energetic balance is likely less favorable, crabs would save energy by being more active during the expected high-temperature phase of the day-light phase-and less during the expected low-temperature phase of the day-dark phase. Our results suggest that endogenous rhythms in intertidal ectotherms generate adaptive behavioral programs to cope with thermoregulatory demands of the intertidal habitat.

  15. QRFP and Its Receptors Regulate Locomotor Activity and Sleep in Zebrafish.

    Science.gov (United States)

    Chen, Audrey; Chiu, Cindy N; Mosser, Eric A; Kahn, Sohini; Spence, Rory; Prober, David A

    2016-02-10

    The hypothalamus plays an important role in regulating sleep, but few hypothalamic sleep-promoting signaling pathways have been identified. Here we demonstrate a role for the neuropeptide QRFP (also known as P518 and 26RFa) and its receptors in regulating sleep in zebrafish, a diurnal vertebrate. We show that QRFP is expressed in ∼10 hypothalamic neurons in zebrafish larvae, which project to the hypothalamus, hindbrain, and spinal cord, including regions that express the two zebrafish QRFP receptor paralogs. We find that the overexpression of QRFP inhibits locomotor activity during the day, whereas mutation of qrfp or its receptors results in increased locomotor activity and decreased sleep during the day. Despite the restriction of these phenotypes to the day, the circadian clock does not regulate qrfp expression, and entrained circadian rhythms are not required for QRFP-induced rest. Instead, we find that QRFP overexpression decreases locomotor activity largely in a light-specific manner. Our results suggest that QRFP signaling plays an important role in promoting sleep and may underlie some aspects of hypothalamic sleep control. The hypothalamus is thought to play a key role in regulating sleep in vertebrate animals, but few sleep-promoting signaling pathways that function in the hypothalamus have been identified. Here we use the zebrafish, a diurnal vertebrate, to functionally and anatomically characterize the neuropeptide QRFP. We show that QRFP is exclusively expressed in a small number of neurons in the larval zebrafish hypothalamus that project widely in the brain. We also show that QRFP overexpression reduces locomotor activity, whereas animals that lack QRFP signaling are more active and sleep less. These results suggest that QRFP signaling participates in the hypothalamic regulation of sleep. Copyright © 2016 the authors 0270-6474/16/361823-18$15.00/0.

  16. Effect of Locomotor Training on Exhaustion of Leg Muscle Activity in Chronic Complete Spinal Cord Injury.

    Science.gov (United States)

    Schrafl-Altermatt, Miriam; Dietz, Volker; Bolliger, Marc

    2017-08-01

    The aim of this study was to evaluate the effect of a continuous locomotor training on leg muscle electromyographic (EMG) exhaustion during assisted stepping movements in a patient with motor complete spinal cord injury (SCI). EMG exhaustion and loss of potentials starts to develop in untrained patients at ∼6 months after injury. In the trained patient examined in this study, exhaustion was also observed but occurred with a delay of several months. In contrast to an untrained patient, no more EMG exhaustion was observed in the very chronic stage. At this time (12 years after injury) a basic locomotor pattern of leg muscle activity of reduced amplitude could still be elicited, but it was resistant to exhaustion and unchanged in amplitude after 12 min of assisted stepping. It is suggested that fatigue-resistant motor units prevail at this stage and can still be activated during stepping as a result of the training.

  17. Conditioned Reinforcement and Locomotor Activating Effects of Caffeine and Ethanol Combinations in Mice

    Science.gov (United States)

    Hilbert, Megan L.T.; May, Christina E.; Griffin, William C.

    2013-01-01

    A growing trend among ethanol drinkers, especially young adults, is to combine caffeinated energy drinks with ethanol during a drinking episode. The primary active ingredient of these mixers is caffeine, which may significantly interact with ethanol. We tested the two hypotheses that caffeine would enhance ethanol-conditioned place preference and also enhance ethanol-stimulated locomotor activity. The interactive pharmacology of ethanol and caffeine was examined in C57BL/6J (B6) mice in a conditioned place preference procedure with 1.75 g/kg ethanol and 3 mg/kg caffeine. Additionally, we used B6 mice to evaluate ethanol/caffeine combinations on locomotor activity using 3 doses of ethanol (1.75, 2.5 and 3.25 g/kg) and 2 two doses of caffeine (3 and 15 mg/kg). Both ethanol and caffeine administered alone increased preference for the drug paired side, though the effect of caffeine was more modest than that of ethanol. The drug combination produced significant place preference itself, but this was not greater than that for ethanol alone. Additionally, the combination of caffeine and ethanol significantly increased locomotion compared to giving either drug alone. The effect was strongest with a stimulatory dose of ethanol (1.75 g/kg) and waned with increasing doses of ethanol. Thus, combinations of caffeine and ethanol had significant conditioned reinforcing and locomotor activating effects in mice. PMID:23872371

  18. Glycogen synthase kinase-3β haploinsufficiency lengthens the circadian locomotor activity period in mice.

    Science.gov (United States)

    Lavoie, Joëlle; Hébert, Marc; Beaulieu, Jean-Martin

    2013-09-15

    The mood stabiliser drug lithium has been reported to impact circadian rhythms in vertebrates. Among several putative therapeutic molecular targets, direct inhibition of glycogen synthase kinase-3 beta (GSK3β) by lithium has been proposed to underlie its effects on circadian physiology. Here we study the effect of GSK3β haploinsufficiency on the circadian locomotor activity in mice during a free-running period in comparison to wildtype littermates (WT). Mice were housed individually to record their circadian wheel running activity and were entrained to a 12h light/12h dark cycle for 14 days and then placed under constant darkness for 14 days to allow free-running. During the free-running phase, the circadian locomotor activity period of GSK3β(+/-) was significantly lengthened (23.83±0.05h) when compared to the WT mice (23.54±0.10h; p=0.0374). No significant difference in locomotor activity was observed. Knowing that GSK3β interacts with most of the core clock components, these data suggest that GSK3β acts as a critical intrinsic regulator of the circadian clock and plays an important role in regulating its period in response to lithium treatment. Copyright © 2013 Elsevier B.V. All rights reserved.

  19. Elimination of Left-Right Reciprocal Coupling in the Adult Lamprey Spinal Cord Abolishes the Generation of Locomotor Activity

    Directory of Open Access Journals (Sweden)

    J. A. Messina

    2017-11-01

    Full Text Available The contribution of left-right reciprocal coupling between spinal locomotor networks to the generation of locomotor activity was tested in adult lampreys. Muscle recordings were made from normal animals as well as from experimental animals with rostral midline (ML spinal lesions (~13%→35% body length, BL, before and after spinal transections (T at 35% BL. Importantly, in the present study actual locomotor movements and muscle burst activity, as well as other motor activity, were initiated in whole animals by descending brain-spinal pathways in response to sensory stimulation of the anterior head. For experimental animals with ML spinal lesions, sensory stimulation could elicit well-coordinated locomotor muscle burst activity, but with some significant differences in the parameters of locomotor activity compared to those for normal animals. Computer models representing normal animals or experimental animals with ML spinal lesions could mimic many of the differences in locomotor activity. For experimental animals with ML and T spinal lesions, right and left rostral hemi-spinal cords, disconnected from intact caudal cord, usually produced tonic or unpatterned muscle activity. Hemi-spinal cords sometimes generated spontaneous or sensory-evoked relatively high frequency “burstlet” activity that probably is analogous to the previously described in vitro “fast rhythm”, which is thought to represent lamprey locomotor activity. However, “burstlet” activity in the present study had parameters and features that were very different than those for lamprey locomotor activity: average frequencies were ~25 Hz, but individual frequencies could be >50 Hz; burst proportions (BPs often varied with cycled time; “burstlet” activity usually was not accompanied by a rostrocaudal phase lag; and following ML spinal lesions alone, “burstlet” activity could occur in the presence or absence of swimming burst activity, suggesting the two were generated

  20. Effects of cocaine on norepinephrine stimulated phosphoinositide hydrolysis and locomotor activity in rat

    International Nuclear Information System (INIS)

    Mosaddeghi, M.

    1989-01-01

    The function of α 1 -adrenoceptors was determined by stimulating cortical tissue slices, which were pre-labeled with [ 3 H]inositol, with norepinephrine (NE) in the presence of 8 mM LiCl. Results of in vitro studies showed that cocaine 10 μM potentiated maximal NE-stimulated PI hydrolysis by 30%. In addition, the EC 50 was decreased from 3.93 ± 0.42 to 1.91 ± 0.31 μM NE. Concentrations of 0.1-100 μM and 0.1-10 μM cocaine enhanced PI hydrolysis stimulated by 0.3 and 3 μM NE, respectively. The concentration-effect curves for NE-stimulated PI hydrolysis were shifted to the right 100-fold in the presence of 0.1 μM prazosin. Cocaine (10 μM) did not potentiate NE-stimulated PI hydrolysis in the presence of 0.1 μM prazosin. [ 3 H]Prazosin saturation and NE [ 3 H]prazosin competition binding studies using crude membrane preparations showed that 10 μM cocaine did not alter binding parameters B max , K d , Hill slope, and IC 50 . Together, these results implied that cocaine in vitro potentiated NE-stimulated PI hydrolysis by blocking NE reuptake. For in vivo studies, the locomotor activity was determined after an acute or chronic injections of either cocaine or saline. Cocaine or saline-treated rats were killed after measurement of the locomotor activity, and NE-stimulated PI hydrolysis was measured. Acute administration of cocaine 3.2-42 mg/kg (i.p.) produced an inverted U shaped dose-response curve on locomotor activity. The peak increase in locomotor activity was at 32 mg/kg cocaine. A dose of 42 mg/kg cocaine produced a significant depression of maximal NE-stimulated PI hydrolysis

  1. Chromosome 1 replacement increases brain orexins and antidepressive measures without increasing locomotor activity.

    Science.gov (United States)

    Feng, Pingfu; Hu, Yufen; Vurbic, Drina; Akladious, Afaf; Strohl, Kingman P

    2014-12-01

    Decreased orexin level has been well demonstrated in patients suffering from narcolepsy, depression accompanied with suicide attempt; obstructive sleep apnea and comorbidity were also demonstrated in these diseases. As C57BL/6J (B6) mice are more "depressed" and have lower brain orexins than A/J mice, B6 mice having chromosome 1 replacement (B6A1 mice) might have restored orexin levels and less depressive behavior. We studied the behavior of 4-6 month old B6, A/J and B6A1 mice with forced swim, tail suspension, and locomotor activity tests. The animals were then sacrificed and hypothalamus and medullas dissected from brain tissue. Orexins-A and -B were determined by radioimmunoassay. Compared with A/J mice, B6 mice displayed several signs of depression, including increased immobility, increased locomotors activity, and decreased orexin A and -B levels in both the hypothalamus and medulla. Compared to B6 mice, B6A1 mice exhibited significantly higher levels of orexins-A and -B in both brain regions. B6A1 mice also exhibited antidepressive features in most of measured variables, including decreased locomotor activity, decreased immobility and increased swim in tail suspension test; compared with B6 mice, however. B6A1 mice also reversed immobility in the early phase of the swim test. In summary, B6 mice exhibited depressive attributes compared with A/J mice, including increased locomotor activity, greater immobility, and decreased brain orexins, these were largely reversed in B6A1 mice. We conclude that orexin levels modulate these B6 behaviors, likely due to expression of A/J alleles on Chromosome 1. Published by Elsevier Ltd.

  2. Music and methamphetamine: conditioned cue-induced increases in locomotor activity and dopamine release in rats.

    Science.gov (United States)

    Polston, J E; Rubbinaccio, H Y; Morra, J T; Sell, E M; Glick, S D

    2011-03-01

    Associations between drugs of abuse and cues facilitate the acquisition and maintenance of addictive behaviors. Although significant research has been done to elucidate the role that simple discriminative or discrete conditioned stimuli (e.g., a tone or a light) play in addiction, less is known about complex environmental cues. The purpose of the present study was to examine the role of a musical conditioned stimulus by assessing locomotor activity and in vivo microdialysis. Two groups of rats were given non-contingent injections of methamphetamine (1.0 mg/kg) or vehicle and placed in standard conditioning chambers. During these conditioning sessions both groups were exposed to a continuous conditioned stimulus, in the form of a musical selection ("Four" by Miles Davis) played repeatedly for 90 min. After seven consecutive conditioning days subjects were given one day of rest, and subsequently tested for locomotor activity or dopamine release in the absence of drugs while the musical conditioned stimulus was continually present. The brain regions examined included the basolateral amygdala, nucleus accumbens, and prefrontal cortex. The results show that music is an effective contextual conditioned stimulus, significantly increasing locomotor activity after repeated association with methamphetamine. Furthermore, this musical conditioned stimulus significantly increased extracellular dopamine levels in the basolateral amygdala and nucleus accumbens. These findings support other evidence showing the importance of these brain regions in conditioned learning paradigms, and demonstrate that music is an effective conditioned stimulus warranting further investigation. Copyright © 2010 Elsevier Inc. All rights reserved.

  3. Effects of lipopolysaccharide and interleukin-6 on cataleptic immobility and locomotor activity in mice.

    Science.gov (United States)

    Bazovkina, Daria V; Tibeikina, Marina A; Kulikov, Alexander V; Popova, Nina K

    2011-01-10

    Catalepsy (animal hypnosis, tonic immobility) is a type of passive defensive behavior. Its exaggerated form is a syndrome of some psychopathological disorders. Numerous neurotransmitters have impact on the regulation of catalepsy. In this paper we demonstrated the involvement of interleukin-6 (IL-6) in the mechanism of cataleptic immobility. Effects of exogenous IL-6 treatment (7.5 and 10μg/kg, i.p) or stimulation of endogenous IL-6 secretion with lipopolysaccharide (LPS) administration (50, 100 and 200μg/kg, i.p.) on catalepsy and locomotor activity were studied in adult C57BL/6 male mice. IL-6 induced catalepsy in 70% (7.5μg/kg) or 72.7% (10μg/kg) of animals with no effect on locomotor activity. LPS administration reduced distance travelled and number of rears in the open field at any dose used, however, only high doses (100 or 200μg/kg) of the toxin induced catalepsy in 50% of mice. This result indicates that IL-6 is involved in the regulation of catalepsy, this effect is specific and does not arise from inhibition of locomotor activity. The study provides a new evidence on participation of IL-6 in mechanisms of abnormal behavior. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  4. Active robotic training improves locomotor function in a stroke survivor

    Directory of Open Access Journals (Sweden)

    Krishnan Chandramouli

    2012-08-01

    Full Text Available Abstract Background Clinical outcomes after robotic training are often not superior to conventional therapy. One key factor responsible for this is the use of control strategies that provide substantial guidance. This strategy not only leads to a reduction in volitional physical effort, but also interferes with motor relearning. Methods We tested the feasibility of a novel training approach (active robotic training using a powered gait orthosis (Lokomat in mitigating post-stroke gait impairments of a 52-year-old male stroke survivor. This gait training paradigm combined patient-cooperative robot-aided walking with a target-tracking task. The training lasted for 4-weeks (12 visits, 3 × per week. The subject’s neuromotor performance and recovery were evaluated using biomechanical, neuromuscular and clinical measures recorded at various time-points (pre-training, post-training, and 6-weeks after training. Results Active robotic training resulted in considerable increase in target-tracking accuracy and reduction in the kinematic variability of ankle trajectory during robot-aided treadmill walking. These improvements also transferred to overground walking as characterized by larger propulsive forces and more symmetric ground reaction forces (GRFs. Training also resulted in improvements in muscle coordination, which resembled patterns observed in healthy controls. These changes were accompanied by a reduction in motor cortical excitability (MCE of the vastus medialis, medial hamstrings, and gluteus medius muscles during treadmill walking. Importantly, active robotic training resulted in substantial improvements in several standard clinical and functional parameters. These improvements persisted during the follow-up evaluation at 6 weeks. Conclusions The results indicate that active robotic training appears to be a promising way of facilitating gait and physical function in moderately impaired stroke survivors.

  5. A new automated method for rat sleep deprivation with minimal confounding effects on corticosterone and locomotor activity

    NARCIS (Netherlands)

    Leenaars, C.H.; Dematteis, M.; Joosten, R.N.J.M.; Eggels, L.; Sandberg, H.; Schirris, M.; Feenstra, M.G.P.; van Someren, E.J.W.

    2011-01-01

    The function of sleep in physiology, behaviour and cognition has become a primary focus of neuroscience. Its study inevitably includes experimental sleep deprivation designs. However, concerns exist regarding confounds like stress, increased locomotor activity levels, and decreased motivation to

  6. Catalase inhibition in the Arcuate nucleus blocks ethanol effects on the locomotor activity of rats.

    Science.gov (United States)

    Sanchis-Segura, Carles; Correa, Mercé; Miquel, Marta; Aragon, Carlos M G

    2005-03-07

    Previous studies have demonstrated that there is a bidirectional modulation of ethanol-induced locomotion produced by drugs that regulate brain catalase activity. In the present study we have assessed the effect in rats of intraperitoneal, intraventricular or intracraneal administration of the catalase inhibitor sodium azide in the locomotor changes observed after ethanol (1 g/kg) administration. Our results show that sodium azide prevents the effects of ethanol in rats locomotion not only when sodium azide was systemically administered but also when it was intraventricularly injected, then confirming that the interaction between catalase and ethanol takes place in Central Nervous System (CNS). Even more interestingly, the same results were observed when sodium azide administration was restricted to the hypothalamic Arcuate nucleus (ARC), a brain region which has one of the highest levels of expression of catalase. Therefore, the results of the present study not only confirm a role for brain catalase in the mediation of ethanol-induced locomotor changes in rodents but also point to the ARC as a major neuroanatomical location for this interaction. These results are in agreement with our reports showing that ethanol-induced locomotor changes are clearly dependent of the ARC integrity and, especially of the POMc-synthesising neurons of this nucleus. According to these data we propose a model in which ethanol oxidation via catalase could produce acetaldehyde into the ARC and to promote a release of beta-endorphins that would activate opioid receptors to produce locomotion and other ethanol-induced neurobehavioural changes.

  7. The effect of kinesio tape on the area of knee on locomotor activity in patients after stroke

    OpenAIRE

    Trčálková, Pavla

    2013-01-01

    Title: The effect of kinesio tape on the area of knee on locomotor activity in patients after stroke Abstract: This bachelor thesis is focused on evaluating the effect of kinesio tape on locomotor activity in patients after stroke. The purpose of this thesis is to compare quality of stereotype of the gait of this patients before and after application of kinesio tape on the area of the knee joint. The theoretical part includes detailed information on kinesio tape, its characteristics, its effe...

  8. Effect of Environmental Conditions and Toxic Compounds on the Locomotor Activity of Pediculus humanus capitis (Phthiraptera: Pediculidae).

    Science.gov (United States)

    Ortega-Insaurralde, I; Toloza, A C; Gonzalez-Audino, P; Mougabure-Cueto, G A; Alvarez-Costa, A; Roca-Acevedo, G; Picollo, M I

    2015-09-01

    In this work, we evaluated the effect of environmental variables such as temperature, humidity, and light on the locomotor activity of Pediculus humanus capitis. In addition, we used selected conditions of temperature, humidity, and light to study the effects of cypermethrin and N,N-diethyl-3-methylbenzamide (DEET) on the locomotor activity of head lice. Head lice increased their locomotor activity in an arena at 30°C compared with activity at 20°C. When we tested the influence of the humidity level, the locomotor activity of head lice showed no significant differences related to humidity level, both at 30°C and 20°C. Concerning light influence, we observed that the higher the intensity of light, the slower the movement of head lice. We also demonstrated that sublethal doses of toxics may alter locomotor activity in adults of head lice. Sublethal doses of cypermethrin induced hyperactivated responses in adult head lice. Sublethal doses of DEET evocated hypoactivated responses in head lice. The observation of stereotyped behavior in head lice elicited by toxic compounds proved that measuring locomotor activity in an experimental set-up where environmental conditions are controlled would be appropriate to evaluate compounds of biological importance, such as molecules involved in the host-parasite interaction and intraspecific relationships. © The Authors 2015. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  9. Analysis of Indonesian Spice Essential Oil Compounds That Inhibit Locomotor Activity in Mice

    Directory of Open Access Journals (Sweden)

    Anas Subarnas

    2011-04-01

    Full Text Available Some fragrance components of spices used for cooking are known to have an effect on human behavior. The aim of this investigation was to examine the effect of the essential oils of basil (Ocimum formacitratum L. leaves, lemongrass (Cymbopogon citrates L. herbs, ki lemo (Litsea cubeba L. bark, and laja gowah (Alpinia malaccencis Roxb. rhizomes on locomotor activity in mice and identify the active component(s that might be responsible for the activity. The effect of the essential oils was studied by a wheel cage method and the active compounds of the essential oils were identified by GC/MS analysis. The essential oils were administered by inhalation at doses of 0.1, 0.3, and 0.5 mL/cage. The results showed that the four essential oils had inhibitory effects on locomotor activity in mice. Inhalation of the essential oils of basil leaves, lemongrass herbs, ki lemo bark, and laja gowah rhizomes showed the highest inhibitory activity at doses of 0.5 (57.64%, 0.1 (55.72%, 0.5 (60.75%, and 0.1 mL/cage (47.09%, respectively. The major volatile compounds 1,8-cineole, α-terpineol, 4-terpineol, citronelol, citronelal, and methyl cinnamate were identified in blood plasma of mice after inhalation of the four oils. These compounds had a significant inhibitory effect on locomotion after inhalation. The volatile compounds of essential oils identified in the blood plasma may correlate with the locomotor-inhibiting properties of the oil when administered by inhalation.

  10. Developmental Deltamethrin Exposure Causes Persistent Changes in Dopaminergic Gene Expression, Neurochemistry, and Locomotor Activity in Zebrafish

    Science.gov (United States)

    Kung, Tiffany S.; Richardson, Jason R.; Cooper, Keith R.; White, Lori A.

    2015-01-01

    Pyrethroids are commonly used insecticides that are considered to pose little risk to human health. However, there is an increasing concern that children are more susceptible to the adverse effects of pesticides. We used the zebrafish model to test the hypothesis that developmental exposure to low doses of the pyrethroid deltamethrin results in persistent alterations in dopaminergic gene expression, neurochemistry, and locomotor activity. Zebrafish embryos were treated with deltamethrin (0.25–0.50 μg/l), at concentrations below the LOAEL, during the embryonic period [3–72 h postfertilization (hpf)], after which transferred to fresh water until the larval stage (2-weeks postfertilization). Deltamethrin exposure resulted in decreased transcript levels of the D1 dopamine (DA) receptor (drd1) and increased levels of tyrosine hydroxylase at 72 hpf. The reduction in drd1 transcripts persisted to the larval stage and was associated with decreased D2 dopamine receptor transcripts. Larval fish, exposed developmentally to deltamethrin, had increased levels of homovanillic acid, a DA metabolite. Since the DA system is involved in locomotor activity, we measured the swim activity of larval fish following a transition to darkness. Developmental exposure to deltamethrin significantly increased larval swim activity which was attenuated by concomitant knockdown of the DA transporter. Acute exposure to methylphenidate, a DA transporter inhibitor, increased swim activity in control larva, while reducing swim activity in larva developmentally exposed to deltamethrin. Developmental exposure to deltamethrin causes locomotor deficits in larval zebrafish, which is likely mediated by dopaminergic dysfunction. This highlights the need to understand the persistent effects of low-dose neurotoxicant exposure during development. PMID:25912032

  11. HIGH ETHANOL DOSE DURING EARLY ADOLESCENCE INDUCES LOCOMOTOR ACTIVATION AND INCREASES SUBSEQUENT ETHANOL INTAKE DURING LATE ADOLESCENCE

    OpenAIRE

    Acevedo, María Belén; Molina, Juan Carlos; Nizhnikov, Michael E.; Spear, Norman E.; Pautassi, Ricardo Marcos

    2010-01-01

    Adolescent initiation of ethanol consumption is associated with subsequent heightened probability of ethanol-use disorders. The present study examined the relationship between motivational sensitivity to ethanol initiation in adolescent rats and later ethanol intake. Experiment 1 determined that ethanol induces locomotor activation shortly after administration but not if tested at a later post-administration interval. In Experiment 2, adolescents were assessed for ethanol-induced locomotor ac...

  12. Effects of cortisol on aggression and locomotor activity in rainbow trout.

    Science.gov (United States)

    Øverli, Øyvind; Kotzian, Susann; Winberg, Svante

    2002-08-01

    Noninvasive administration of cortisol through the diet resulted in relatively rapid (Aggressive behavior was also inhibited by long-term cortisol treatment, but not by short-term exposure to cortisol. Cortisol treatment had no effect on locomotor activity in undisturbed fish, indicating that the behavioral effects of cortisol were mediated through interaction with other signal systems activated during the simulated territorial intrusion test. This study demonstrates for the first time that cortisol has time- and context-dependent effects on behavior in teleost fish.

  13. Fluoxetine and aripiprazole treatment following prenatal immune activation exert longstanding effects on rat locomotor response.

    Science.gov (United States)

    Richtand, Neil M; Ahlbrand, Rebecca; Horn, Paul; Tambyraja, Rabindra; Grainger, Molly; Bronson, Stefanie L; McNamara, Robert K

    2012-05-15

    Studies characterizing treatment interventions in a naturalistic setting suggest that antidepressant and antipsychotic medications may be equally effective in improving clinical outcome in individuals at high risk for first-episode psychosis. Of interest, both beneficial as well as potentially adverse effects have been observed following fluoxetine treatment in a mouse prenatal immune activation model of relevance to psychosis prevention. We sought to extend those findings by examining the effects of fluoxetine, as well as the antipsychotic medication aripiprazole, in a rat prenatal immune activation model. Pregnant Sprague-Dawley rats were injected with poly I:C or saline on gestational day 14. Offspring of poly I:C and saline-treated dams received fluoxetine (10.0 mg/kg/d), aripiprazole (0.66 mg/kg/d), or vehicle from postnatal days 35 to 70. Locomotor responses to novelty, saline injection, and amphetamine (1 and 5 mg/kg) were determined at three months, i.e., 21 days following drug discontinuation. Both fluoxetine and aripiprazole had beneficial effects on behavioral response to amphetamine (1 mg/kg) at 3 months, ameliorating the impact of prenatal immune activation on offspring of poly I:C-treated dams. Significantly, both drugs also exerted effects in offspring of control (saline-treated) dams on locomotor response to injection. Fluoxetine and aripiprazole pretreatment of poly I:C offspring from postnatal days 35 to 70 stabilized response to amphetamine exposure persisting through 3 months of age, similar to earlier findings in mice that fluoxetine treatment following prenatal immune activation prevented altered locomotor response to amphetamine. The current data also confirm earlier findings of potential adverse behavioral effects in offspring of control dams following treatment with fluoxetine and antipsychotic medications, highlighting the potential for both therapeutic as well as safety concerns with exposure to preventive pharmacological treatments over

  14. Automated locomotor activity monitoring as a quality control assay for mass-reared tephritid flies.

    Science.gov (United States)

    Dominiak, Bernard C; Fanson, Benjamin G; Collins, Samuel R; Taylor, Phillip W

    2014-02-01

    The Sterile Insect Technique (SIT) requires vast numbers of consistently high quality insects to be produced over long periods. Quality control (QC) procedures are critical to effective SIT, both providing quality assurance and warning of operational deficiencies. We here present a potential new QC assay for mass rearing of Queensland fruit flies (Bactrocera tryoni Froggatt) for SIT; locomotor activity monitoring. We investigated whether automated locomotor activity monitors (LAMs) that simply detect how often a fly passes an infrared sensor in a glass tube might provide similar insights but with much greater economy. Activity levels were generally lower for females than for males, and declined over five days in the monitor for both sexes. Female activity levels were not affected by irradiation, but males irradiated at 60 or 70 Gy had reduced activity levels compared with unirradiated controls. We also found some evidence that mild heat shock of pupae results in adults with reduced activity. LAM offers a convenient, effective and economical assay to probe such changes. © 2013 Society of Chemical Industry.

  15. Rhythmic arm swing enhances patterned locomotor-like muscle activity in passively moved lower extremities

    Science.gov (United States)

    Ogawa, Tetsuya; Sato, Takahiko; Ogata, Toru; Yamamoto, Shin-Ichiro; Nakazawa, Kimitaka; Kawashima, Noritaka

    2015-01-01

    The use of driven gait orthosis (DGO) has drawn attention in gait rehabilitation for patients after central nervous system (CNS) lesions. By imposing a passive locomotor-like kinematic pattern, the neural mechanisms responsible for locomotion can be activated as in a normal gait. To further enhance this activity, discussions on possible intervention are necessary. Given the possible functional linkages between the upper and lower limbs, we investigated in healthy subjects the degree of modification in the lower limb muscles during DGO-induced passive gait by the addition of swing movement in the upper extremity. The results clearly showed that muscle activity in the ankle dorsiflexor TA muscle was significantly enhanced when the passive locomotor-like movement was accompanied by arm swing movement. The modifications in the TA activity were not a general increase through the stride cycles, but were observed under particular phases as in normal gaits. Voluntary effort to swing the arms may have certain effects on the modification of the muscle activity. The results provide clinical implications regarding the usefulness of voluntary arm swing movement as a possible intervention in passive gait training using DGO, since ordinary gait training using DGO does not induce spontaneous arm swing movement despite its known influence on the lower limb movement. PMID:25742956

  16. The effects of opioid drugs on dopamine mediated locomotor activity in rats

    International Nuclear Information System (INIS)

    Leathern, L.L.

    1986-12-01

    Opioid drugs influence various behavioural parameters including locomotor activity in experimental animals. The interaction between the opioid and dopaminergic systems is one possible explanation for the effect of opioid drugs on locomotor activity. In this study behavioural and biochemical assays were done to investigate the interaction between the opioid and dopaminergic systems. Behavioural studies were done by measurement of locomotor activity (LA) of rats after acute or chronic pretreatment with opioid and/or dopaminergic drugs. Biochemical studies were in the form of radioligand binding assays, the effect on the number (Bmax) and affinity (K D ) of receptors was measured after chronic pretreatment with opioid and/or dopaminergic drugs. The opioid drugs used are morphine, nalbuphine and naloxone. Dopaminergic drugs used included: agonists-apomorphine and piribedil; antagonists-pimozide, haloperidol, chlorpromazine. In the acute situation increased LA was obtained with morphine and the DA agonists. A correlation between the behavioural and biochemical assays was found. Chronic pretreatment with morphine enhanced apomorphine induced LA, this supersensitivity was also measured as an increased receptor density (Bmax) of D2 receptors in the striatum. Chronic morphine pretreatment caused a decrease in morphine induced LA, while this subsensitivity was not apparent in the ligand binding assays - where no change in receptor number was observed. Chronic naloxone pretreatment enhanced morphine induced LA, as well as increased the Bmax of opioid receptors in the whole brain. It is concluded that an interaction between the opioid and dopaminergic systems does exist, and may account for the mechanism of action of the opioids

  17. α6β2 nicotinic acetylcholine receptors influence locomotor activity and ethanol consumption.

    Science.gov (United States)

    Kamens, Helen M; Peck, Colette; Garrity, Caitlin; Gechlik, Alex; Jenkins, Brenita C; Rajan, Akshat

    2017-06-01

    Nicotinic acetylcholine receptors (nAChRs) in the mesolimbic dopamine system have been implicated in ethanol behaviors. In particular, work in genetically engineered mice has demonstrated that α6-containing nAChRs are involved in ethanol consumption and sedation. A limitation of these studies is that the alteration in the receptor was present throughout development. The recently described α6β2 antagonist, N,N-decane-1,10-diyl-bis-3-picolinium diiodide (bPiDI), now makes it possible to test for the involvement of these receptors using a pharmacological approach. The aim of this study was to examine the role of α6β2 nAChRs in ethanol behaviors using a pharmacological approach. Adolescent C57BL/6J mice were treated with bPiDI 30 min prior to testing the mice for binge-like ethanol consumption in the drinking-in-the-dark (DID) test, ethanol-induced motor incoordination using the balance beam, and ethanol-induced sedation using the Loss of Righting Reflex (LORR) paradigm. Adolescent animals were chosen because they express a high amount of α6 mRNA relative to adult animals. Control studies were also performed to determine the effect of bPiDI on locomotor activity and ethanol metabolism. Female mice treated with 20 mg/kg bPiDI had reduced locomotor activity compared to saline-treated animals during the first 30 min following an acute injection. Pretreatment with the α6β2 antagonist reduced adolescent ethanol consumption but also reduced saccharin consumption. No significant effects were observed on ethanol-induced ataxia, sedation, or metabolism. This study provides evidence that α6β2 nAChRs are involved in locomotor activity as well as ethanol and saccharin consumption in adolescent animals. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Mouse shoulder morphology responds to locomotor activity and the kinematic differences of climbing and running.

    Science.gov (United States)

    Green, David J; Richmond, Brian G; Miran, Sara L

    2012-12-01

    Mechanical loads play a significant role in determining long bone shape and strength, but less work has explored how these loads influence flat bones like the scapula, which has been shown to vary with locomotor preference among primate taxa. Here, we tested the effects of voluntary running and climbing exercise in mice to examine how the mechanical loads borne from different locomotor patterns influence shoulder morphological development. Ninety-nine female wild-type mice were distributed equally among sedentary control, activity-wheel running, and vertical climbing experimental conditions. Running mice had the lowest body masses, larger intrinsic shoulder muscles, and the most pronounced differences in scapular size and shape relative to the other groups. Climbing mouse scapular morphology also differed significantly from the control individuals, but these differences were not as marked as those between the running and control mice. This might be attributable in part to greater levels of activity in the wheel-runners relative to the climbers. Additionally, climbing mice held their bodies closer to the substrate and maintained more flexed limbs and posterior hand positions compared with the kinematics of running. As a result, climbers differed significantly from both the running and control mice in developing a relatively broader infraspinous region, which is likely related to preferential recruitment of the infraspinatus and teres minor muscles to maintain flexed shoulder postures. The results of this study demonstrate that variation in activity level and type of locomotor regime over a significant portion of the life history influences muscle and bone development in the shoulder. Copyright © 2012 Wiley Periodicals, Inc.

  19. Oxytocin decreases cocaine taking, cocaine seeking, and locomotor activity in female rats

    OpenAIRE

    Leong, Kah-Chung; Zhou, Luyi; Ghee, Shannon M.; See, Ronald E.; Reichel, Carmela M.

    2016-01-01

    Oxytocin has been shown to decrease cocaine taking and seeking in male rats, suggesting potential treatment efficacy for drug addiction. In the present study, we extended these findings to the assessment of cocaine seeking and taking in female rats. Further, we made direct comparisons of oxytocin’s impact on cocaine induced locomotor activity in both males and females. In females, systemic oxytocin (0.3, 1.0, 3.0 mg/kg) attenuated lever pressing for cocaine during self-administration and oxyt...

  20. Locomotor activity, object exploration and space preference in children with autism and Down syndrome.

    Science.gov (United States)

    Kawa, Rafał; Pisula, Ewa

    2010-01-01

    There have been ambiguous accounts of exploration in children with intellectual disabilities with respect to the course of that exploration, and in particular the relationship between the features of explored objects and exploratory behaviour. It is unclear whether reduced exploratory activity seen with object exploration but not with locomotor activity is autism-specific or if it is also present in children with other disabilities. The purpose of the present study was to compare preschool children with autism with their peers with Down syndrome and typical development in terms of locomotor activity and object exploration and to determine whether the complexity of explored objects affects the course of exploration activity in children with autism. In total there were 27 children in the study. The experimental room was divided into three zones equipped with experimental objects providing visual stimulation of varying levels of complexity. Our results indicate that children with autism and Down syndrome differ from children with typical development in terms of some measures of object exploration (i.e. looking at objects) and time spent in the zone with the most visually complex objects.

  1. Activation of the GABAB receptor prevents nicotine-induced locomotor stimulation in mice

    Directory of Open Access Journals (Sweden)

    Carla eLobina

    2011-12-01

    Full Text Available Recent studies demonstrated that activation of the GABAB receptor, either by means of orthosteric agonists or positive allosteric modulators (PAMs, inhibited different nicotine-related behaviors, including intravenous self-administration and conditioned place preference, in rodents. The present study investigated whether the anti-nicotine effects of the GABAB receptor agonist, baclofen, and GABAB PAMs, CGP7930 and GS39783, extend to nicotine stimulant effects. To this end, CD1 mice were initially treated with baclofen (0, 1.25, and 2.5 mg/kg, i.p., CGP7930 (0, 25, and 50 mg/kg, i.g., or GS39783 (0, 25, and 50 mg/kg, i.g., then treated with nicotine (0 and 0.05 mg/kg, s.c., and finally exposed to an automated apparatus for recording of locomotor activity. Pretreatment with doses of baclofen, CGP7930, or GS39783 that did not alter locomotor activity when given with nicotine vehicle fully prevented hyperlocomotion induced by 0.05 mg/kg nicotine. These data extend to nicotine stimulant effects the capacity of baclofen and GABAB PAMs to block the reinforcing, motivational, and rewarding properties of nicotine. These data strengthen the hypothesis that activation of the GABAB receptor may represent a potentially useful, anti-smoking therapeutic strategy.

  2. Mice Lacking EGR1 Have Impaired Clock Gene (BMAL1) Oscillation, Locomotor Activity, and Body Temperature.

    Science.gov (United States)

    Riedel, Casper Schwartz; Georg, Birgitte; Jørgensen, Henrik L; Hannibal, Jens; Fahrenkrug, Jan

    2018-01-01

    Early growth response transcription factor 1 (EGR1) is expressed in the suprachiasmatic nucleus (SCN) after light stimulation. We used EGR1-deficient mice to address the role of EGR1 in the clock function and light-induced resetting of the clock. The diurnal rhythms of expression of the clock genes BMAL1 and PER1 in the SCN were evaluated by semi-quantitative in situ hybridization. We found no difference in the expression of PER1 mRNA between wildtype and EGR1-deficient mice; however, the daily rhythm of BMAL1 mRNA was completely abolished in the EGR1-deficient mice. In addition, we evaluated the circadian running wheel activity, telemetric locomotor activity, and core body temperature of the mice. Loss of EGR1 neither altered light-induced phase shifts at subjective night nor affected negative masking. Overall, circadian light entrainment was found in EGR1-deficient mice but they displayed a reduced locomotor activity and an altered temperature regulation compared to wild type mice. When placed in running wheels, a subpopulation of EGR1-deficient mice displayed a more disrupted activity rhythm with no measurable endogenous period length (tau). In conclusion, the present study provides the first evidence that the circadian clock in the SCN is disturbed in mice deficient of EGR1.

  3. Temporal phasing of locomotor activity, heart rate rhythmicity, and core body temperature is disrupted in VIP receptor 2-deficient mice

    DEFF Research Database (Denmark)

    Hannibal, Jens; Hsiung, Hansen M; Fahrenkrug, Jan

    2011-01-01

    to that of wild-type mice. The use of telemetric devices to measure circadian locomotor activity, temperature, and heart rate, together with the classical determination of circadian rhythms of wheel-running activity, raises questions about how representative wheel-running activity may be of other behavioral...... these observations with observations made from mice examined by wheel-running activity. The study demonstrates that VPAC2 signaling is necessary for a functional circadian clock driving locomotor activity, core body temperature, and heart rate rhythmicity, since VPAC2-deficient mice lose the rhythms in all three...

  4. Changes in supraspinal activation patterns following robotic locomotor therapy in motor-incomplete spinal cord injury.

    Science.gov (United States)

    Winchester, Patricia; McColl, Roderick; Querry, Ross; Foreman, Nathan; Mosby, James; Tansey, Keith; Williamson, Jon

    2005-12-01

    Body weight-supported treadmill training (BWSTT) is a task-specific rehabilitation strategy that enhances functional locomotion in patients following spinal cord injury (SCI). Supraspinal centers may play an important role in the recovery of over-ground locomotor function in patients with motor-incomplete SCI. The purpose of this study was to evaluate the potential for supraspinal reorganization associated with 12 weeks of robotic BWSTT using functional magnetic resonance imaging (fMRI). Four men with motor-incomplete SCI participated in this study. Time since onset ranged from 14 weeks to 48 months post-SCI injury. All subjects were trained with BWSTT 3 times weekly for 12 weeks. This training was preceded and followed by fMRI study of supraspinal activity during a movement task. Testing of locomotor disability included the Walking Index for Spinal Cord Injury (WISCI II) and over-ground gait speed. All subjects demonstrated some degree of change in the blood-oxygen-level-dependent (BOLD) signal following BWSTT. fMRI results demonstrated greater activation in sensorimotor cortical regions (S1, S2) and cerebellar regions following BWSTT. Intensive task-specific rehabilitative training, such as robotic BWSTT, can promote supraspinal plasticity in the motor centers known to be involved in locomotion. Furthermore, improvement in over-ground locomotion is accompanied by an increased activation of the cerebellum.

  5. Effect of electrolytic lesion of the dorsomedial striatum on sexual behaviour and locomotor activity in rats.

    Science.gov (United States)

    Ortiz-Pulido, R; Hernández-Briones, Z S; Tamariz-Rodríguez, A; Hernández, M E; Aranda-Abreu, G E; Coria-Avila, G A; Manzo, J; García, L I

    2017-06-01

    Cortical motor areas are influenced not only by peripheral sensory afferents and prefrontal association areas, but also by the basal ganglia, specifically the striatum. The dorsomedial striatum (DMS) and dorsolateral striatum are involved in both spatial and stimulus-response learning; however, each of these areas may mediate different components of learning. The aim of the study is to determine the effect of electrolytic lesion to the DMS on the learning and performance of sexual behaviour and locomotor activity in male rats. Once the subjects had learned to perform motor tests of balance, maze navigation, ramp ascent, and sexual behaviour, they underwent electrolytic lesion to the DMS. Five days later, the tests were repeated on 2 occasions and researchers compared performance latencies for each test. Average latency values for performance on the maze and balance tests were higher after the lesion. However, the average values for the ramp test and for sexual behaviour did not differ between groups. Electrolytic lesion of the DMS modifies the performance of locomotor activity (maze test and balance), but not of sexual behaviour. Copyright © 2015 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

  6. Radioprotection, locomotor activity and consummatory behavior of mice administered synthetic trehalose dimycolate (S-TDM)

    International Nuclear Information System (INIS)

    McChesney, D.G.; Landauer, M.R.; Davis, H.D.

    1990-01-01

    The biological response modifier, S-TDM, administered in doses of 100, 200, 400 and 800 ug/mouse 24 hours before a LD80/30 dose (5.6 Gy at 0.4 Gy-MLT/minute) of radiation (neutron:gamma double-bond 1) resulted in survival of 100%, 60%, 89% and 20% respectively. Because of the radioprotective efficacy of this immunomodulator, the behavioral effects of S-TDM were investigated. Locomotor activity, food intake, water consumption, and body weight were examined using female B6D2F1 mice. At doses of 100-400 ug/mouse locomotor activity decreased within 4 hours of administration and returned to control values by 2.5 days postinjection. Food and water intake were significantly depressed at doses of 100, 200, and 400 ug/mouse on the day following drug administration and recovered in 1 day. Body weight was significantly decreased in the 100 and 200 ug/mouse groups for 2 days and in the 400 ug/mouse for 3 days following injection of S-TDM. These results indicate that there is short-term reversible toxicity in mice administered S-TDM at doses of 100, 200, and 400 ug/mouse

  7. Effects of Lactuca sativa extract on exploratory behavior pattern, locomotor activity and anxiety in mice

    Directory of Open Access Journals (Sweden)

    S.N. Harsha

    2012-05-01

    Full Text Available Objective: To evaluate antianxiety property of Lactuca sativa, an important and commonly used leafy vegetable known for its medicinal properties belongs to Asteraceae family. Methods: Elevated plus maze (EPM, open field test (OFT, rat exposure test, hyponeophagia and marble burying test were performed in mice models to assess the exploratory behaviour and to assess anxiolytic property of hydro-alcohol extract of Lactuca sativa. Diazepam (1 mg/kg body wt. served as the standard anxiolytic agent for all the tests. The dried extract of the plant leaf in doses of 100, 200 and 400 mg/kg body weight was administered orally to mice for duration of 15 or 30 days and evaluated exploratory behaviour, locomotor and anxiolytic activities. Results: Time spent and number of entries into the open arm was measured in EPM followed by total locomotor activity in OFT and latency to enter the food zone in hyponeophagia. Conclusions: The study suggested that hydro-alcohol extract of Lactuca sativa leaves possess potent anxiolytic property.

  8. Regulation by orexin of feeding behaviour and locomotor activity in the goldfish.

    Science.gov (United States)

    Nakamachi, T; Matsuda, K; Maruyama, K; Miura, T; Uchiyama, M; Funahashi, H; Sakurai, T; Shioda, S

    2006-04-01

    Orexin is a hypothalamic neuropeptide that is implicated in the regulation of feeding behaviour and the sleep-wakefulness cycle in mammals. However, in spite of a growing body of knowledge concerning orexin in mammals, the orexin system and its function have not been well studied in lower vertebrates. In the present study, we first examined the effect of feeding status on the orexin-like immunoreactivity (orexin-LI) and the expression of orexin mRNA in the goldfish brain. The number of cells showing orexin-LI in the hypothalamus of goldfish brain showed a significant increase in fasted fish and a significant decrease in glucose-injected fish. The expression level of orexin mRNA in the brains of fasted fish increased compared to that of fed fish. We also examined the effect of an i.c.v. injection of orexin or an anti-orexin serum on food intake and locomotor activity in the goldfish. Administration of orexin by i.c.v. injection induced a significant increase of food intake and locomotor activity, whereas i.p. injection of glucose or i.c.v. injection of anti-orexin serum decreased food consumption. These results indicate that the orexin functions as an orexigenic factor in the goldfish brain.

  9. Locomotor Activity and Body Temperature Patterns over a Temperature Gradient in the Highveld Mole-Rat (Cryptomys hottentotus pretoriae).

    Science.gov (United States)

    Haupt, Meghan; Bennett, Nigel C; Oosthuizen, Maria K

    2017-01-01

    African mole-rats are strictly subterranean mammals that live in extensive burrow systems. High humidity levels in the burrows prevent mole-rats from thermoregulating using evaporative cooling. However, the relatively stable environment of the burrows promotes moderate temperatures and small daily temperature fluctuations. Mole-rats therefore display a relatively wide range of thermoregulation abilities. Some species cannot maintain their body temperatures at a constant level, whereas others employ behavioural thermoregulation. Here we test the effect of ambient temperature on locomotor activity and body temperature, and the relationship between the two parameters, in the highveld mole-rat. We exposed mole-rats to a 12L:12D and a DD light cycle at ambient temperatures of 30°C, 25°C and 20°C while locomotor activity and body temperature were measured simultaneously. In addition, we investigated the endogenous rhythms of locomotor activity and body temperature at different ambient temperatures. Mole-rats displayed nocturnal activity at all three ambient temperatures and were most active at 20°C, but least active at 30°C. Body temperature was highest at 30°C and lowest at 20°C, and the daily cycle was highly correlated with locomotor activity. We show that the mole-rats have endogenous rhythms for both locomotor activity and body temperature. However, the endogenous body temperature rhythm appears to be less robust compared to the locomotor activity rhythm. Female mole-rats appear to be more sensitive to temperature changes than males, increased heterothermy is evident at lower ambient temperatures, whilst males show smaller variation in their body temperatures with changing ambient temperatures. Mole-rats may rely more heavily on behavioural thermoregulation as it is more energy efficient in an already challenging environment.

  10. Circadian rhythms of body temperature and locomotor activity in the antelope ground squirrel, Ammospermophilus leucurus.

    Science.gov (United States)

    Refinetti, Roberto; Kenagy, G J

    2018-02-01

    We studied circadian rhythms of body temperature and locomotor activity in antelope ground squirrels (Ammospermophilus leucurus) under laboratory conditions of a 12L:12D light-dark cycle and in constant darkness. Antelope ground squirrels are diurnally active and, exceptionally among ground squirrels and other closely related members of the squirrel family in general, they do not hibernate. Daily oscillations in body temperature consisted of a rise in temperature during the daytime activity phase of the circadian cycle and a decrease in temperature during the nighttime rest phase. The body temperature rhythms were robust (71% of maximal strength) with a daily range of oscillation of 4.6°C, a daytime mean of 38.7°C, and a nighttime mean of 34.1°C (24-h overall mean 36.4°C). The body temperature rhythm persisted in continuous darkness with a free-running period of 24.2h. This pattern is similar to that of hibernating species of ground squirrels but with a wave form more similar to that of non-hibernating rodents. Daily oscillations in body temperature were correlated with individual bouts of activity, but daytime temperatures were higher than nighttime temperatures even when comparing short episodes of nocturnal activity that were as intense as diurnal activity. This suggests that although muscular thermogenesis associated with locomotor activity can modify the level of body temperature, the circadian rhythm of body temperature is not simply a consequence of the circadian rhythm of activity. Copyright © 2018 Elsevier Ltd. All rights reserved.

  11. Temporal phasing of locomotor activity, heart rate rhythmicity, and core body temperature is disrupted in VIP receptor 2-deficient mice

    DEFF Research Database (Denmark)

    Hannibal, Jens; Hsiung, Hansen M; Fahrenkrug, Jan

    2011-01-01

    Neurons of the brain's biological clock located in the hypothalamic suprachiasmatic nucleus (SCN) generate circadian rhythms of physiology (core body temperature, hormone secretion, locomotor activity, sleep/wake, and heart rate) with distinct temporal phasing when entrained by the light/dark (LD...... these observations with observations made from mice examined by wheel-running activity. The study demonstrates that VPAC2 signaling is necessary for a functional circadian clock driving locomotor activity, core body temperature, and heart rate rhythmicity, since VPAC2-deficient mice lose the rhythms in all three...

  12. Effects of Resveratrol on Daily Rhythms of Locomotor Activity and Body Temperature in Young and Aged Grey Mouse Lemurs

    Directory of Open Access Journals (Sweden)

    Fabien Pifferi

    2013-01-01

    Full Text Available In several species, resveratrol, a polyphenolic compound, activates sirtuin proteins implicated in the regulation of energy balance and biological clock processes. To demonstrate the effect of resveratrol on clock function in an aged primate, young and aged mouse lemurs (Microcebus murinus were studied over a 4-week dietary supplementation with resveratrol. Spontaneous locomotor activity and daily variations in body temperature were continuously recorded. Reduction in locomotor activity onset and changes in body temperature rhythm in resveratrol-supplemented aged animals suggest an improved synchronisation on the light-dark cycle. Resveratrol could be a good candidate to restore the circadian rhythms in the elderly.

  13. Speed dependency in α-motoneuron activity and locomotor modules in human locomotion: indirect evidence for phylogenetically conserved spinal circuits.

    Science.gov (United States)

    Yokoyama, Hikaru; Ogawa, Tetsuya; Shinya, Masahiro; Kawashima, Noritaka; Nakazawa, Kimitaka

    2017-03-29

    Coordinated locomotor muscle activity is generated by the spinal central pattern generators (CPGs). Vertebrate studies have demonstrated the following two characteristics of the speed control mechanisms of the spinal CPGs: (i) rostral segment activation is indispensable for achieving high-speed locomotion; and (ii) specific combinations between spinal interneuronal modules and motoneuron (MN) pools are sequentially activated with increasing speed. Here, to investigate whether similar control mechanisms exist in humans, we examined spinal neural activity during varied-speed locomotion by mapping the distribution of MN activity in the spinal cord and extracting locomotor modules, which generate basic MN activation patterns. The MN activation patterns and the locomotor modules were analysed from multi-muscle electromyographic recordings. The reconstructed MN activity patterns were divided into the following three patterns depending on the speed of locomotion: slow walking, fast walking and running. During these three activation patterns, the proportion of the activity in rostral segments to that in caudal segments increased as locomotion speed increased. Additionally, the different MN activation patterns were generated by distinct combinations of locomotor modules. These results are consistent with the speed control mechanisms observed in vertebrates, suggesting phylogenetically conserved spinal mechanisms of neural control of locomotion. © 2017 The Author(s).

  14. Citrus flavonoid, naringenin, increases locomotor activity and reduces diacylglycerol accumulation in skeletal muscle of obese ovariectomized mice.

    Science.gov (United States)

    Ke, Jia-Yu; Cole, Rachel M; Hamad, Essam M; Hsiao, Yung-Hsuan; Cotten, Bradley M; Powell, Kimerly A; Belury, Martha A

    2016-02-01

    Estrogen deficiency has been associated with central obesity, muscle loss and metabolic syndrome in postmenopausal women. This study assessed naringenin accumulation in tissues and investigated the hypothesis that naringenin reverses diet-induced metabolic disturbances in obese ovariectomized mice. In study 1, we measured naringenin concentrations in plasma, liver, perigonadal and subcutaneous adipose tissues, and muscle of ovariectomized C57BL/6J female mice after 11 weeks of naringenin supplementation. Naringenin accumulated 5-12 times more in mice fed a 3% naringenin diet than in mice fed a 1% naringenin diet. In study 2, ovariectomized mice were fed a high-fat diet (60 kcal% fat) for 11 weeks and half of the mice were then supplemented with 3% naringenin for another 11 weeks. Dietary naringenin suppressed weight gain, lowered hyperglycemia and decreased intra-abdominal adiposity evaluated by magnetic resonance imaging. Naringenin-fed mice exhibited elevated locomotor activity monitored by infrared beam breaks, maintained muscle mass and reduced muscle diacylglycerol content. Real-time PCR analysis in muscle revealed decreased mRNA level for genes involved in de novo lipogenesis, lipolysis and triglyceride synthesis/storage. Long-term 3% naringenin supplementation resulted in significant naringenin accumulation in plasma and tissues, associated with attenuated metabolic dysregulation and muscle loss in obese ovariectomized mice. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Distribution of networks generating and coordinating locomotor activity in the neonatal rat spinal cord in vitro: a lesion study

    DEFF Research Database (Denmark)

    Kjaerulff, O; Kiehn, O

    1996-01-01

    , these pathways were distributed along the lumbar enlargement. Both lateral and ventral funiculi were sufficient to coordinate activity in the rostral and caudal regions. We conclude that the networks organizing locomotor-related activity in the spinal cord of the newborn rat are distributed....

  16. Running behavior and its energy cost in mice selectively bred for high voluntary locomotor activity.

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    Rezende, Enrico L; Gomes, Fernando R; Chappell, Mark A; Garland, Theodore

    2009-01-01

    Locomotion is central to behavior and intrinsic to many fitness-critical activities (e.g., migration, foraging), and it competes with other life-history components for energy. However, detailed analyses of how changes in locomotor activity and running behavior affect energy budgets are scarce. We quantified these effects in four replicate lines of house mice that have been selectively bred for high voluntary wheel running (S lines) and in their four nonselected control lines (C lines). We monitored wheel speeds and oxygen consumption for 24-48 h to determine daily energy expenditure (DEE), resting metabolic rate (RMR), locomotor costs, and running behavior (bout characteristics). Daily running distances increased roughly 50%-90% in S lines in response to selection. After we controlled for body mass effects, selection resulted in a 23% increase in DEE in males and a 6% increase in females. Total activity costs (DEE - RMR) accounted for 50%-60% of DEE in both S and C lines and were 29% higher in S males and 5% higher in S females compared with their C counterparts. Energetic costs of increased daily running distances differed between sexes because S females evolved higher running distances by running faster with little change in time spent running, while S males also spent 40% more time running than C males. This increase in time spent running impinged on high energy costs because the majority of running costs stemmed from "postural costs" (the difference between RMR and the zero-speed intercept of the speed vs. metabolic rate relationship). No statistical differences in these traits were detected between S and C females, suggesting that large changes in locomotor behavior do not necessarily effect overall energy budgets. Running behavior also differed between sexes: within S lines, males ran with more but shorter bouts than females. Our results indicate that selection effects on energy budgets can differ dramatically between sexes and that energetic constraints in S

  17. Effects of Risperidone and Paliperidone Pretreatment on Locomotor Response Following Prenatal Immune Activation

    Science.gov (United States)

    Richtand, Neil M.; Ahlbrand, Rebecca; Horn, Paul; Stanford, Kevin; Bronson, Stefanie L.; McNamara, Robert K.

    2011-01-01

    Aim Limited data are available regarding pharmacological characteristics of effective interventions for psychosis prevention. Enrollment challenges in psychosis prevention trials impede screening diverse interventions for efficacy. Relevant animal models could help circumvent this barrier. We previously described prevention with risperidone of abnormal behavior following neonatal hippocampal lesion. We aimed to extend those findings evaluating risperidone and paliperidone following prenatal immune activation, a developmental model of a schizophrenia risk factor. We evaluated a later developmental time point to determine persistent effects of drug treatment. Methods Pregnant Sprague-Dawley rats were injected with poly I:C or saline on gestational day 14. Offspring of poly I:C and saline treated dams received risperidone (0.45 mg/kg/d), paliperidone (0.05 mg/kg/d), or vehicle from postnatal days 35 to 70. Locomotor responses to novelty, saline injection, and amphetamine (1 and 5 mg/kg) were determined at three months, i.e., 21 days following antipsychotic discontinuation. Results Risperidone and paliperidone had persistent effects on behavioral response to amphetamine (1 mg/kg) at 3 months, ameliorating the impact of prenatal immune activation on offspring of poly I:C-treated dams. Risperidone, but not paliperidone, also exerted persistent effects in offspring of saline-treated dams on locomotor response to saline and amphetamine (5 mg/kg) injection. Conclusions Risperidone and paliperidone pretreatment of poly I:C offspring during peri-pubertal development stabilized response to amphetamine exposure persisting into early adulthood. Prenatal immune activation provides a model for evaluating effects of an environmental risk factor for schizophrenia, and has potential utility for identifying pharmacological approaches to early intervention. PMID:21440257

  18. Increased amphetamine-induced locomotor activity, sensitization, and accumbal dopamine release in M5 muscarinic receptor knockout mice

    DEFF Research Database (Denmark)

    Schmidt, Lene S; Miller, Anthony D; Lester, Deranda B

    2010-01-01

    showed that M(5) receptor knockout (M (5) (-/-) ) mice are less sensitive to the reinforcing properties of addictive drugs. MATERIALS AND METHODS: Here, we investigate the role of M(5) receptors in the effects of amphetamine and cocaine on locomotor activity, locomotor sensitization, and dopamine release...... and locomotor sensitization were enhanced in M (5) (-/-) mice, while the effects of cocaine were similar in M (5) (-/-) and wild-type mice. RESULTS: Consistent with the behavioral results, amphetamine-, but not cocaine, -elicited dopamine release in nucleus accumbens was enhanced in M (5) (-/-) mice. DISCUSSION......: The different effects of amphetamine and cocaine in M (5) (-/-) mice may be due to the divergent pharmacological profile of the two drugs, where amphetamine, but not cocaine, is able to release intracellular stores of dopamine. In conclusion, we show here for the first time that amphetamine...

  19. Monitoring and Analyzing of Circadian and Ultradian Locomotor Activity Based on Raspberry-Pi

    Directory of Open Access Journals (Sweden)

    Vittorio Pasquali

    2016-09-01

    Full Text Available A new device based on the Raspberry-Pi to monitor the locomotion of Arctic marine invertebrates and to analyze chronobiologic data has been made, tested and deployed. The device uses infrared sensors to monitor and record the locomotor activity of the animals, which is later analyzed. The software package consists of two separate scripts: the first designed to manage the acquisition and the evolution of the experiment, the second designed to generate actograms and perform various analyses to detect periodicity in the data (e.g., Fourier power spectra, chi-squared periodograms, and Lomb–Scargle periodograms. The data acquisition hardware and the software has been previously tested during an Arctic mission with an arctic marine invertebrate.

  20. Cardiovascular responses to locomotor activity and feeding in unrestrained three-toed sloths, Bradypus variegatus

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    D.P.F. Duarte

    2004-10-01

    Full Text Available Heart rate (HR and systolic (SBP, diastolic (DBP and mean (MBP blood pressure were recorded by biotelemetry in nine conscious unrestrained sloths for 1 min every 15 min over a 24-h period. The animals were allowed to freely move in an acoustically isolated and temperature-controlled (24 ± 1ºC experimental room with light-dark cycle (12/12 h. Behavior was closely monitored through a unidirectional visor and classified as resting (sitting or suspended, feeding (chewing and swallowing embauba leaves, Cecropia adenops, or locomotor activity around the tree trunk or on the room floor. Locomotor activity caused statistically significant increases in SBP (+8%, from 121 ± 22 to 131 ± 18 mmHg, DBP (+7%, from 86 ± 17 to 92 ± 10 mmHg, MBP (+8%, from 97 ± 19 to 105 ± 12 mmHg, and HR (+14%, from 84 ± 15 to 96 ± 15 bpm compared to resting values, indicating a possible major influence of the autonomic nervous system on the modulation of cardiac function during this behavior. During feeding, the increase in blood pressure was even higher (SBP +27%, from 119 ± 21 to 151 ± 21 mmHg; DBP +21%, from 85 ± 16 to 103 ± 15 mmHg; MBP +24%, from 96 ± 17 to 119 ± 17 mmHg, while HR remained at 14% (from 84 ± 15 to 96 ± 10 bpm above resting values. The proportionally greater increase in blood pressure than in HR during feeding suggests an increase in peripheral vascular resistance as part of the overall response to this behavior.

  1. Syngeneic B16F10 Melanoma Causes Cachexia and Impaired Skeletal Muscle Strength and Locomotor Activity in Mice

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    Fabrício A. Voltarelli

    2017-09-01

    Full Text Available Muscle wasting has been emerging as one of the principal components of cancer cachexia, leading to progressive impairment of work capacity. Despite early stages melanomas rarely promotes weight loss, the appearance of metastatic and/or solid tumor melanoma can leads to cachexia development. Here, we investigated the B16F10 tumor-induced cachexia and its contribution to muscle strength and locomotor-like activity impairment. C57BL/6 mice were subcutaneously injected with 5 × 104 B16F10 melanoma cells or PBS as a Sham negative control. Tumor growth was monitored during a period of 28 days. Compared to Sham mice, tumor group depicts a loss of skeletal muscle, as well as significantly reduced muscle grip strength and epididymal fat mass. This data are in agreement with mild to severe catabolic host response promoted by elevated serum tumor necrosis factor-alpha (TNF-α, interleukin-6 (IL-6 and lactate dehydrogenase (LDH activity. Tumor implantation has also compromised general locomotor activity and decreased exploratory behavior. Likewise, muscle loss, and elevated inflammatory interleukin were associated to muscle strength loss and locomotor activity impairment. In conclusion, our data demonstrated that subcutaneous B16F10 melanoma tumor-driven catabolic state in response to a pro-inflammatory environment that is associated with impaired skeletal muscle strength and decreased locomotor activity in tumor-bearing mice.

  2. The effect of 5-HT1A receptor agonists on locomotor activity in the guinea-pig.

    Science.gov (United States)

    Evenden, J L

    1994-07-01

    1. The present study examined the effects of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), flesinoxan, ipsapirone and buspirone, all agonists at the 5-HT1A receptor, on the locomotor activity of guinea-pigs. The effects of these drugs were contrasted with those of the non-selective 5-HT agonist, 5-methoxy-N,N-dimethyl tryptamine (5-MeO-DMT) and the dopamine D2 antagonist, raclopride. 2. 8-OH-DPAT, flesinoxan and 5-MeO-DMT markedly increased the locomotor activity of naive, unhabituated guinea-pigs in a dose-dependent manner. Buspirone also did so, although to a lesser extent and for a shorter time. The doses at which this effect was seen were higher than those normally employed in rats. Ipsapirone and raclopride had no significant effects on locomotor activity. 3. The locomotor activity increasing effect of 1.0 mg kg-1 8-OH-DPAT was blocked by the selective 5-HT1A antagonist (S)-UH-301 (3.0 and 10.0 mg kg-1), but not by (-)-alprenolol (15.0 mg kg-1). Ipsapirone (30.0 mg kg-1) and raclopride (3.0 mg kg-1) antagonized 8-OH-DPAT-induced locomotor activity but only to a small extent. The 5-HT reuptake inhibitor, zimelidine (10.0 mg kg-1) had no effect. 4. The effect of the 5-HT1A agonists in the guinea-pig contrasts with the effects of 8-OH-DPAT on the locomotor activity of unhabituated rats and mice tested in the same apparatus, but are similar to the effects of 8-OH-DPAT on habituated rats, which show a low baseline of activity. 5. These results support the suggestion that 5-HTIA agonists may have an intrinsic activating effect which may be masked by other effects of the drug (e.g. hypothermia, 5-HT syndrome). The rank ordering of the 5-HTIA agonists also suggests that the degree to which the drugs increase locomotor activity is related to their agonist efficacy at the postsynaptic 5-HTIA receptor.

  3. Estradiol facilitation of cocaine-induced locomotor sensitization in female rats requires activation of mGluR5.

    Science.gov (United States)

    Martinez, Luis A; Peterson, Brittni M; Meisel, Robert L; Mermelstein, Paul G

    2014-09-01

    In comparison to men, women exhibit enhanced responsiveness to the stimulating and addictive properties of cocaine. A growing body of evidence implicates the steroid hormone estradiol in mediating this sex difference, yet the mechanisms underlying estradiol enhancement of behavioral responses to cocaine in females are not known. Recently, we have found that estrogen receptor alpha (ERα) functionally couples with the metabotropic glutamate receptor 5 (mGluR5) to mediate the effects of estradiol on both cellular activation as well as dendritic spine plasticity in brain regions involved in cocaine-induced behavioral sensitization. Thus, we sought to determine whether mGluR5 activation is required for the facilitative effects of estradiol on locomotor responses to cocaine. To test this hypothesis, ovariectomized (OVX) female rats were tested for locomotor activity on the first and fifth days of daily systemic injections of cocaine. For the 2 days prior to each locomotor test, animals were injected with the mGluR5 antagonist MPEP (or vehicle) and estradiol (or oil). MPEP treatment blocked the facilitative effects of estradiol on cocaine-induced locomotor sensitization, without affecting acute responses to cocaine or the inhibitory actions of estradiol on weight gain. Considered together, these data indicate that mGluR5 activation is critical for the actions of estradiol on cocaine-induced behavioral sensitization. Copyright © 2014 Elsevier B.V. All rights reserved.

  4. Circadian Clock Protein Content and Daily Rhythm of Locomotor Activity Are Altered after Chronic Exposure to Lead in Rat

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    Mariam Sabbar

    2017-09-01

    Full Text Available Lead exposure has been reported to produce many clinical features, including parkinsonism. However, its consequences on the circadian rhythms are still unknown. Here we aimed to examine the circadian rhythms of locomotor activity following lead intoxication and investigate the mechanisms by which lead may induce alterations of circadian rhythms in rats. Male Wistar rats were injected with lead or sodium acetate (10 mg/kg/day, i.p. during 4 weeks. Both groups were tested in the “open field” to quantify the exploratory activity and in the rotarod to evaluate motor coordination. Then, animals were submitted to continuous 24 h recordings of locomotor activity under 14/10 Light/dark (14/10 LD cycle and in complete darkness (DD. At the end of experiments, the clock proteins BMAL1, PER1-2, and CRY1-2 were assayed in the suprachiasmatic nucleus (SCN using immunohistochemistry. We showed that lead significantly reduced the number of crossing in the open field, impaired motor coordination and altered the daily locomotor activity rhythm. When the LD cycle was advanced by 6 h, both groups adjusted their daily locomotor activity to the new LD cycle with high onset variability in lead-intoxicated rats compared to controls. Lead also led to a decrease in the number of immunoreactive cells (ir- of BMAL1, PER1, and PER2 without affecting the number of ir-CRY1 and ir-CRY2 cells in the SCN. Our data provide strong evidence that lead intoxication disturbs the rhythm of locomotor activity and alters clock proteins expression in the SCN. They contribute to the understanding of the mechanism by which lead induce circadian rhythms disturbances.

  5. Locomotor activity and the expression of orexin A and orexin B in aged female rhesus macaques.

    Science.gov (United States)

    Luna, Selva L; Brown, Donald I; Eghlidi, Dominique H; Kohama, Steven G; Urbanski, Henryk F

    2017-02-01

    Reduced activity has been linked to age-associated physiological changes but the underlying root cause is unclear. The goal of the present study was to compare the orexin neuronal system of old (23-29 years) female rhesus macaques with either active or sedentary 24-hour locomotor activity patterns. Using immunohistochemistry, we counted the number of orexin A and orexin B neurons in the lateral hypothalamic area of each animal. Overall, we observed no difference in the distribution pattern or number of either orexin A or orexin B immune-positive neurons between animals in the 2 groups. Thus, reduced activity in the elderly is unlikely to stem from a loss of orexin neuronal perikarya in the lateral hypothalamic area. This, however, does not rule out the possibility that the reduced activity stems from reduced orexin neuronal projections to arousal centers of the brain, such as the locus coeruleus, or from attenuated release of orexin. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Optogenetic Activation of the Excitatory Neurons Expressing CaMKIIα in the Ventral Tegmental Area Upregulates the Locomotor Activity of Free Behaving Rats

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    Songchao Guo

    2014-01-01

    Full Text Available The ventral tegmental area (VTA plays an important role in motivation and motor activity of mammals. Previous studies have reported that electrical stimulations of the VTA’s neuronal projections were able to upregulate the locomotor activity of behaving rats. However, which types of neurons in the VTA that take part in the activation remain elusive. In this paper we employed optogenetic technique to selectively activate the excitatory neurons expressing CaMKIIα in the VTA region and induced a higher locomotor activity for free behaving rats. Further behavioral studies indicated that reward learning mediated in the enhancement of the rat locomotor activity. Finally the immunohistochemistry studies explored that the excitatory neurons under the optogenetic activation in VTA were partly dopaminergic that may participate as a vital role in the optogenetic activation of the locomotor activity. In total, our study provided an optogenetic approach to selectively upregulate the locomotor activity of free behaving rats, thus facilitating both neuroscience researches and neural engineering such as animal robotics in the future.

  7. Effect of Error Augmentation on Brain Activation and Motor Learning of a Complex Locomotor Task

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    Laura Marchal-Crespo

    2017-09-01

    Full Text Available Up to date, the functional gains obtained after robot-aided gait rehabilitation training are limited. Error augmenting strategies have a great potential to enhance motor learning of simple motor tasks. However, little is known about the effect of these error modulating strategies on complex tasks, such as relearning to walk after a neurologic accident. Additionally, neuroimaging evaluation of brain regions involved in learning processes could provide valuable information on behavioral outcomes. We investigated the effect of robotic training strategies that augment errors—error amplification and random force disturbance—and training without perturbations on brain activation and motor learning of a complex locomotor task. Thirty-four healthy subjects performed the experiment with a robotic stepper (MARCOS in a 1.5 T MR scanner. The task consisted in tracking a Lissajous figure presented on a display by coordinating the legs in a gait-like movement pattern. Behavioral results showed that training without perturbations enhanced motor learning in initially less skilled subjects, while error amplification benefited better-skilled subjects. Training with error amplification, however, hampered transfer of learning. Randomly disturbing forces induced learning and promoted transfer in all subjects, probably because the unexpected forces increased subjects' attention. Functional MRI revealed main effects of training strategy and skill level during training. A main effect of training strategy was seen in brain regions typically associated with motor control and learning, such as, the basal ganglia, cerebellum, intraparietal sulcus, and angular gyrus. Especially, random disturbance and no perturbation lead to stronger brain activation in similar brain regions than error amplification. Skill-level related effects were observed in the IPS, in parts of the superior parietal lobe (SPL, i.e., precuneus, and temporal cortex. These neuroimaging findings

  8. Mouse short- and long-term locomotor activity analyzed by video tracking software.

    Science.gov (United States)

    York, Jason M; Blevins, Neil A; McNeil, Leslie K; Freund, Gregory G

    2013-06-20

    Locomotor activity (LMA) is a simple and easily performed measurement of behavior in mice and other rodents. Improvements in video tracking software (VTS) have allowed it to be coupled to LMA testing, dramatically improving specificity and sensitivity when compared to the line crossings method with manual scoring. In addition, VTS enables high-throughput experimentation. While similar to automated video tracking used for the open field test (OFT), LMA testing is unique in that it allows mice to remain in their home cage and does not utilize the anxiogenic stimulus of bright lighting during the active phase of the light-dark cycle. Traditionally, LMA has been used for short periods of time (mins), while longer movement studies (hrs-days) have often used implanted transmitters and biotelemetry. With the option of real-time tracking, long-, like short-term LMA testing, can now be conducted using videography. Long-term LMA testing requires a specialized, but easily constructed, cage so that food and water (which is usually positioned on the cage top) does not obstruct videography. Importantly, videography and VTS allows for the quantification of parameters, such as path of mouse movement, that are difficult or unfeasible to measure with line crossing and/or biotelemetry. In sum, LMA testing coupled to VTS affords a more complete description of mouse movement and the ability to examine locomotion over an extended period of time.

  9. EPOC and the energetics of brief locomotor activity in Mus domesticus.

    Science.gov (United States)

    Baker, E J; Gleeson, T T

    1998-02-01

    Excess post-exercise oxygen consumption (EPOC) is normally not considered in determinations of the metabolic cost of activity. This approach overlooks an important energetic cost that an animal incurs as a result of activity. To examine the importance of EPOC, we determined how the energetic cost of locomotion was affected by activity of short duration and high intensity. Mice were run at maximum speed on a treadmill while enclosed in an open-flow respirometry system. After sprinting for 5, 15, 30, or 60 sec, each mouse was allowed to recover while remaining enclosed in the respirometry chamber. Exercise oxygen consumption (EOC), the volume of oxygen consumed during the exercise, increased linearly with sprint duration. EPOC was determined as the volume of oxygen consumed after exercise ended until rest was reached. EPOC volumes were found to be constant following 5-60 sec of activity and accounted for > or = 90% of the total metabolic cost. The average EPOC volume of all treatments was 0.76 +/- 0.456 ml O2.gm-1. The net cost of activity (Cact), which considers both EOC and EPOC, decreased as sprint duration increased and varied between 500 ml O2.g-1.km-1 for 5 sec to 30 ml O2.g-1.km-1 for 60 sec of activity. The values for Cact were 15 to 250 times higher than traditional estimates of locomotor costs. From these data, it can be concluded that (1) EPOC is not affected by short exercise durations; (2) EPOC is an important energetic consideration when exercise durations are short; and (3) the metabolic costs of brief, vigorous locomotion may be much higher than previously estimated.

  10. Dietary omega-3 fatty acids and locomotor activity in an animal model of attention deficit hyperactivity disorder (ADHD

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    Klaus W. Lange

    2013-06-01

    Full Text Available ABSTRACTBackground: Attention deficit hyperactivity disorder (ADHD is the most frequent behavioral disorder of childhood and is characterized by hyperactivity, attention problems and impulsivity. Pharmacological and behavioral therapies have been shown to be effective. In addition, the role of dietary compounds in the etiology and possibly the treatment of ADHD has attracted increasing attention. For example, the lack of dietary essential fatty acids has been suggested to be associated with symptoms of ADHD in humans.Objective: To investigate the effects of omega-3 polyunsaturated fatty acids (n-3 PUFAs on locomotor activity in the spontaneously hypertensive rat (SHR which has been proposed as an animal model of ADHD.Methods: Two groups of randomly assigned spontaneously hypertensive rats were fed with either n-3 PUFA-deficient or n-3 PUFA-enriched food (based on AIN93G for six weeks and this was continued during the phase of behavioral testing. Locomotor activity was subsequently assessed using an open field test.Results: The results showed a marked difference in locomotor activity between the two groups of SHRs. In comparison with rats fed with n-3 deficient food, the animals on an n-3 enriched diet showed a statistically significant decrease in motor activity as assessed by the distance traveled.Conclusions: The present study demonstrates a marked reduction in locomotor activity following an n-3 PUFA-enriched diet in SHRs, i.e. the dietary enrichment with n-3 PUFAs reduced the motor activity in an established animal model of ADHD. Dietary n-3 PUFAs may therefore play a role in the pathophysiology of ADHD.Key words: omega-3 polyunsaturated fatty acids, attention deficit hyperactivity disorder, ADHD, animal model, spontaneously hypertensive rat, SHR, motor activity

  11. Temporal phasing of locomotor activity, heart rate rhythmicity, and core body temperature is disrupted in VIP receptor 2-deficient mice

    DEFF Research Database (Denmark)

    Hannibal, Jens; Hsiung, Hansen M; Fahrenkrug, Jan

    2011-01-01

    Neurons of the brain's biological clock located in the hypothalamic suprachiasmatic nucleus (SCN) generate circadian rhythms of physiology (core body temperature, hormone secretion, locomotor activity, sleep/wake, and heart rate) with distinct temporal phasing when entrained by the light/dark (LD...... these observations with observations made from mice examined by wheel-running activity. The study demonstrates that VPAC2 signaling is necessary for a functional circadian clock driving locomotor activity, core body temperature, and heart rate rhythmicity, since VPAC2-deficient mice lose the rhythms in all three...... parameters when placed under constant conditions (of either light or darkness). Furthermore, although 24-h rhythms for three parameters are retained in VPAC2-deficient mice during the LD cycle, the temperature rhythm displays markedly altered time course and profile, rising earlier and peaking ~4-6 h prior...

  12. Intermittent long-wavelength red light increases the period of daily locomotor activity in mice

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    Hughes Amanda M

    2005-05-01

    Full Text Available Abstract Background We observed that a dim, red light-emitting diode (LED triggered by activity increased the circadian periods of lab mice compared to constant darkness. It is known that the circadian period of rats increases when vigorous wheel-running triggers full-spectrum lighting; however, spectral sensitivity of photoreceptors in mice suggests little or no response to red light. Thus, we decided to test the following hypotheses: dim red light illumination triggered by activity (LEDfb increases the circadian period of mice compared to constant dark (DD; covering the LED prevents the effect on period; and DBA2/J mice have a different response to LEDfb than C57BL6/J mice. Methods The irradiance spectra of the LEDs were determined by spectrophotometer. Locomotor activity of C57BL/6J and DBA/2J mice was monitored by passive-infrared sensors and circadian period was calculated from the last 10 days under each light condition. For constant dark (DD, LEDs were switched off. For LED feedback (LEDfb, the red LED came on when the mouse was active and switched off seconds after activity stopped. For taped LED the red LED was switched on but covered with black tape. Single and multifactorial ANOVAs and post-hoc t-tests were done. Results The circadian period of mice was longer under LEDfb than under DD. Blocking the light eliminated the effect. There was no difference in period change in response to LEDfb between C57BL/6 and DBA/2 mice. Conclusion An increase in mouse circadian period due to dim far-red light (1 lux at 652 nm exposure was unexpected. Since blocking the light stopped the response, sound from the sensor's electronics was not the impetus of the response. The results suggest that red light as background illumination should be avoided, and indicator diodes on passive infrared motion sensors should be switched off.

  13. The 28-day exposure to fenpropathrin decreases locomotor activity and reduces activity of antioxidant enzymes in mice brains.

    Science.gov (United States)

    Nieradko-Iwanicka, Barbara; Borzęcki, Andrzej

    2016-04-01

    Fenpropathrin (Fen) is a pyrethroid (Pyr) insecticide. Pyrs are used in veterinary medicine, in agriculture and for domestic purposes. As their use increases, new questions about their side effects and mode of action in non-target organisms arise. The objective of this work was to characterize dose-response relationship for in vivo motor function and memory in mice exposed to Fen for 28 days and to assess its influence on activity of antioxidant enzymes in mice brains. The experiment was performed using 64 female mice. Fen at the dose of 11.9mg/kg of body mass, 5.95mg/kg or 2.38mg/kg was administered ip to the mice for 28 consecutive days. Motor function and spatial working memory were tested on days 7, 14 and 28. On day 29, the animals were sacrificed and brains were used to determine activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx). Fen significantly decreased locomotor activity in mice receiving the highest dose at every stage of the experiment. Lower doses reduced locomotion on days 7 and 14. Fen did not produce memory impairment. A decrease in activities of SOD and GPx was recorded in mice brains. The decrease of SOD activity in mice brains results from direct inhibition of the enzyme by Fen and/or increased utilization due to excessive free radical formation in conditions of Fen-induced oxidative stress. The reduction in GPx activity is probably due to limited glutathione availability. The reduced locomotor activity is a behavioral demonstration of Fen-induced damage in the dopaminergic system. Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  14. CD146 deletion in the nervous system impairs appetite, locomotor activity and spatial learning in mice.

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    Tao Tu

    Full Text Available Cell adhesion molecules (CAMs are crucial effectors for the development and maintenance of the nervous system. Mutations in human CAM genes are linked to brain disorders and psychological diseases, and CAM knockout mice always exhibit similar behavioral abnormalities. CD146 is a CAM of the immunoglobulin superfamily that interacts with Neurite Outgrowth Factor and involved in neurite extension in vitro. However, little is known about its in vivo function in the nervous system. In this study, we used a murine CD146 nervous system knockout (CD146(ns-ko model. We found that the brains of some CD146(ns-ko mice were malformed with small olfactory bulbs. CD146(ns-ko mice exhibited lower body weights and smaller food intake when compared with wild type littermates. Importantly, behavior tests revealed that CD146(ns-ko mice exhibited significant decreased locomotor activity and impaired capacity for spatial learning and memory. Our results demonstrate that CD146 is important for mammalian nervous system development and proper behavior patterns.

  15. Attenuated food anticipatory activity and abnormal circadian locomotor rhythms in Rgs16 knockdown mice.

    Directory of Open Access Journals (Sweden)

    Naoto Hayasaka

    Full Text Available Regulators of G protein signaling (RGS are a multi-functional protein family, which functions in part as GTPase-activating proteins (GAPs of G protein α-subunits to terminate G protein signaling. Previous studies have demonstrated that the Rgs16 transcripts exhibit robust circadian rhythms both in the suprachiasmatic nucleus (SCN, the master circadian light-entrainable oscillator (LEO of the hypothalamus, and in the liver. To investigate the role of RGS16 in the circadian clock in vivo, we generated two independent transgenic mouse lines using lentiviral vectors expressing short hairpin RNA (shRNA targeting the Rgs16 mRNA. The knockdown mice demonstrated significantly shorter free-running period of locomotor activity rhythms and reduced total activity as compared to the wild-type siblings. In addition, when feeding was restricted during the daytime, food-entrainable oscillator (FEO-driven elevated food-anticipatory activity (FAA observed prior to the scheduled feeding time was significantly attenuated in the knockdown mice. Whereas the restricted feeding phase-advanced the rhythmic expression of the Per2 clock gene in liver and thalamus in the wild-type animals, the above phase shift was not observed in the knockdown mice. This is the first in vivo demonstration that a common regulator of G protein signaling is involved in the two separate, but interactive circadian timing systems, LEO and FEO. The present study also suggests that liver and/or thalamus regulate the food-entrained circadian behavior through G protein-mediated signal transduction pathway(s.

  16. Conditioned place preference and locomotor activity in response to methylphenidate, amphetamine and cocaine in mice lacking dopamine D4 receptors

    Energy Technology Data Exchange (ETDEWEB)

    Thanos, P.K.; Thanos, P.K.; Bermeo, C.; Rubinstein, M.; Suchland, K.L.; Wang, G.-J.; Grandy, D.K.; Volkow, N.D.

    2010-05-01

    Methylphenidate (MP) and amphetamine (AMPH) are the most frequently prescribed medications for the treatment of attention-deficit/hyperactivity disorder (ADHD). Both drugs are believed to derive their therapeutic benefit by virtue of their dopamine (DA)-enhancing effects, yet an explanation for the observation that some patients with ADHD respond well to one medication but not to the other remains elusive. The dopaminergic effects of MP and AMPH are also thought to underlie their reinforcing properties and ultimately their abuse. Polymorphisms in the human gene that codes for the DA D4 receptor (D4R) have been repeatedly associated with ADHD and may correlate with the therapeutic as well as the reinforcing effects of responses to these psychostimulant medications. Conditioned place preference (CPP) for MP, AMPH and cocaine were evaluated in wild-type (WT) mice and their genetically engineered littermates, congenic on the C57Bl/6J background, that completely lack D4Rs (knockout or KO). In addition, the locomotor activity in these mice during the conditioning phase of CPP was tested in the CPP chambers. D4 receptor KO and WT mice showed CPP and increased locomotor activity in response to each of the three psychostimulants tested. D4R differentially modulates the CPP responses to MP, AMPH and cocaine. While the D4R genotype affected CPP responses to MP (high dose only) and AMPH (low dose only) it had no effects on cocaine. Inasmuch as CPP is considered an indicator of sensitivity to reinforcing responses to drugs these data suggest a significant but limited role of D4Rs in modulating conditioning responses to MP and AMPH. In the locomotor test, D4 receptor KO mice displayed attenuated increases in AMPH-induced locomotor activity whereas responses to cocaine and MP did not differ. These results suggest distinct mechanisms for D4 receptor modulation of the reinforcing (perhaps via attenuating dopaminergic signalling) and locomotor properties of these stimulant drugs

  17. Cocaine-induced locomotor activity is increased by prior handling in adolescent but not adult female rats

    OpenAIRE

    Maldonado, Antoniette M.; Kirstein, Cheryl L.

    2005-01-01

    Adolescence is a period of transition that is associated with increased levels of stress and a heightened propensity to initiate drug use. Neuronal development is still occurring during this transitional period, which includes the continued development of the dopamine system during the adolescent period. In the present study, the effects of pre-test handling on cocaine-induced locomotor activity were investigated among female adolescent and young adult rats upon presentation to a novel enviro...

  18. Impairment of locomotor activity induced by the novel N-acylhydrazone derivatives LASSBio-785 and LASSBio-786 in mice

    International Nuclear Information System (INIS)

    Silva, G.A.P.; Kummerle, A.E.; Antunes, F.; Fraga, C.A.M.; Barreiro, E.J.; Zapata-Sudo, G.; Sudo, R.T.

    2013-01-01

    The N-acylhydrazone (NAH) analogues N-methyl 2-thienylidene 3,4-benzoylhydrazine (LASSBio-785) and N-benzyl 2-thienylidene 3,4-benzoylhydrazine (LASSBio-786) were prepared from 2-thienylidene 3,4-methylenedioxybenzoylhydrazine (LASSBio-294). The ability of LASSBio-785 and LASSBio-786 to decrease central nervous system activity was investigated in male Swiss mice. LASSBio-785 or LASSBio-786 (30 mg/kg, ip) reduced locomotor activity from 209 ± 26 (control) to 140 ± 18 (P < 0.05) or 146 ± 15 crossings/min (P < 0.05), respectively. LASSBio-785 (15 or 30 mg/kg, iv) also reduced locomotor activity from 200 ± 15 to 116 ± 29 (P < 0.05) or 60 ± 16 crossings/min (P < 0.01), respectively. Likewise, LASSBio-786 (15 or 30 mg/kg, iv) reduced locomotor activity from 200 ± 15 to 127 ± 10 (P < 0.01) or 96 ± 14 crossings/min (P < 0.01), respectively. Pretreatment with flumazenil (20 mg/kg, ip) prevented the locomotor impairment induced by NAH analogues (15 mg/kg, iv), providing evidence that the benzodiazepine (BDZ) receptor is involved. This finding was supported by the structural similarity of NAH analogues to midazolam. However, LASSBio-785 showed weak binding to the BDZ receptor. LASSBio-785 or LASSBio-786 (30 mg/kg, ip, n = 10) increased pentobarbital-induced sleeping time from 42 ± 5 (DMSO) to 66 ± 6 (P < 0.05) or 75 ± 4 min (P < 0.05), respectively. The dose required to achieve 50% hypnosis (HD 50 ) following iv injection of LASSBio-785 or LASSBio-786 was 15.8 or 9.5 mg/kg, respectively. These data suggest that both NAH analogues might be useful for the development of new neuroactive drugs for the treatment of insomnia or for use in conjunction with general anesthesia

  19. Impairment of locomotor activity induced by the novel N-acylhydrazone derivatives LASSBio-785 and LASSBio-786 in mice

    Energy Technology Data Exchange (ETDEWEB)

    Silva, G.A.P. [Programa de Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ (Brazil); Kummerle, A.E. [Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ (Brazil); Antunes, F. [Programa de Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ (Brazil); Fraga, C.A.M.; Barreiro, E.J. [Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ (Brazil); Programa de Pós-Graduação em Química, Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ (Brazil); Zapata-Sudo, G.; Sudo, R.T. [Programa de Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ (Brazil)

    2013-03-19

    The N-acylhydrazone (NAH) analogues N-methyl 2-thienylidene 3,4-benzoylhydrazine (LASSBio-785) and N-benzyl 2-thienylidene 3,4-benzoylhydrazine (LASSBio-786) were prepared from 2-thienylidene 3,4-methylenedioxybenzoylhydrazine (LASSBio-294). The ability of LASSBio-785 and LASSBio-786 to decrease central nervous system activity was investigated in male Swiss mice. LASSBio-785 or LASSBio-786 (30 mg/kg, ip) reduced locomotor activity from 209 ± 26 (control) to 140 ± 18 (P < 0.05) or 146 ± 15 crossings/min (P < 0.05), respectively. LASSBio-785 (15 or 30 mg/kg, iv) also reduced locomotor activity from 200 ± 15 to 116 ± 29 (P < 0.05) or 60 ± 16 crossings/min (P < 0.01), respectively. Likewise, LASSBio-786 (15 or 30 mg/kg, iv) reduced locomotor activity from 200 ± 15 to 127 ± 10 (P < 0.01) or 96 ± 14 crossings/min (P < 0.01), respectively. Pretreatment with flumazenil (20 mg/kg, ip) prevented the locomotor impairment induced by NAH analogues (15 mg/kg, iv), providing evidence that the benzodiazepine (BDZ) receptor is involved. This finding was supported by the structural similarity of NAH analogues to midazolam. However, LASSBio-785 showed weak binding to the BDZ receptor. LASSBio-785 or LASSBio-786 (30 mg/kg, ip, n = 10) increased pentobarbital-induced sleeping time from 42 ± 5 (DMSO) to 66 ± 6 (P < 0.05) or 75 ± 4 min (P < 0.05), respectively. The dose required to achieve 50% hypnosis (HD{sub 50}) following iv injection of LASSBio-785 or LASSBio-786 was 15.8 or 9.5 mg/kg, respectively. These data suggest that both NAH analogues might be useful for the development of new neuroactive drugs for the treatment of insomnia or for use in conjunction with general anesthesia.

  20. The possible interaction of dopamine system in nucleus accumbens shell and glutamate system of prelimbic region on locomotor activity in rat

    Directory of Open Access Journals (Sweden)

    Hatam Ahmadi

    2013-06-01

    Full Text Available Background: Nucleus accumbens (NAc and prefrontal cortex (PFC dopaminergic and glutamatergic systems are involved in regulating of locomotor activity behaviors. This study has investigated the interaction of NAc shell dopaminergic system and prelimbic glutamatergic systems in regulating locomotor activity and related parameters. Methods: The aim of this study was the effect the drugs injection interaction in the brain of male Wistar rats on locomotor activity and related parameters, in the order of this purpose, open field apparatus that automatically recorded locomotor activity was employed. Unilateral intra-cerebral injection of drugs was done. Results: Unilateral intra-prelimbic injection of D-AP7 (N-methyl-D-aspartic acid= NMDA receptor antagonist; 0.25, 0.5 and 1μg/μl did not alter locomotor activity behaviors. However, infusion of NMDA (0.9μg/μl in this region increased locomotor activity (P<0.01, whereas decreased rearing (P<0.01 and grooming (P<0.01 which was blocked by D-AP7 (0.25μg/μl (P<0.01. Moreover, unilateral infusion of SCH23390 (dopamine D1 receptor antagonist; 0.25, 0.5 and 1μg/μl into the left NAc shell did not alter locomotor activity. However, injection of SKF38393 (dopamine D1 receptor agonist; 4μg/μl into the left NAc shell increased locomotor activity (P<0.05 which was blocked by SCH23390 (0.25μg/μl (P<0.01. Furthermore, the subthreshold dose infusion of SCH23390 (0.25μg/μl into the left NAc shell reduced the effect of intra- prelimbic NMDA on locomotor activity (P<0.01. In addition, intra-NAc shell administration of the subthreshold dose of SKF38393 (1μg/μl potentiated the middle dose (P<0.05, whereas decreased the higher dose of intra-left prelimbic NMDA response (P<0.05 on locomotor activity. Conclusion: The results suggested a modulatory effect of the NAc shell dopaminergic system on increased locomotor activity by activating glutamate system in prelimbic.

  1. Application of the Copenhagen Soccer Test in high-level women players - locomotor activities, physiological response and sprint performance

    DEFF Research Database (Denmark)

    Bendiksen, Mads; Pettersen, Svein Arne; Ingebrigtsen, Jørgen

    2013-01-01

    We evaluated the physiological response, sprint performance and technical ability in various phases of the Copenhagen Soccer Test for Women (CSTw) and investigated whether the locomotor activities of the CSTw were comparable to competitive match-play (CM). Physiological measurements and physical....../technical assessments were performed during CSTw for eleven Norwegian high-level women soccer players. The activity pattern during CSTw and CM was monitored using the ZXY tracking system. No differences were observed between CSTw and CM with regards to total distance covered (10093±94 and 9674±191m), high intensity...

  2. Effect of age and severity of cognitive dysfunction on spontaneous activity in pet dogs - part 1: locomotor and exploratory behaviour.

    Science.gov (United States)

    Rosado, B; González-Martínez, A; Pesini, P; García-Belenguer, S; Palacio, J; Villegas, A; Suárez, M-L; Santamarina, G; Sarasa, M

    2012-11-01

    Age-related cognitive dysfunction syndrome (CDS) has been reported in dogs and it is considered a natural model for Alzheimer's disease in humans. Changes in spontaneous activity (including locomotor and exploratory behaviour) and social responsiveness have been related to the age and cognitive status of kennel-reared Beagle dogs. The aim of this study was to assess the influence of age and severity of CDS on locomotor and exploratory behaviour of privately owned dogs. This is the first part of a two-part report on spontaneous activity in pet dogs. An open-field (OF) test and a curiosity test were administered at baseline and 6 months later to young (1-4 years, n=9), middle-aged (5-8 years, n=9), cognitively unimpaired aged (≥ 9 years, n=31), and cognitively impaired aged ( ≥ 9 years, n=36) animals. Classification of cognitive status was carried out using an owner-based observational questionnaire, and in the cognitively impaired group, the dogs were categorised as having either mild or severe cognitive impairment. Dogs were recorded during sessions in the testing room and the video-recordings were subsequently analysed. The severity of CDS (but not age) influenced locomotion and exploratory behaviour so that the more severe the impairment, the higher the locomotor activity and frequency of corner-directed (aimless) behaviours, and the lower the frequency of door-aimed activities. Curiosity directed toward novel stimuli exhibited an age-dependent decline although severely affected animals displayed more sniffing episodes directed towards the objects. OF activity did not change after 6 months. Testing aged pet dogs for spontaneous behaviour might help to better characterise cognitively affected individuals. Copyright © 2012 Elsevier Ltd. All rights reserved.

  3. Comparison of caffeine-induced locomotor activity between adolescent and adult rats

    OpenAIRE

    Marin, Marcelo Tadeu [UNESP; Zancheta, Roberta [UNESP; Paro, Ana H. [UNESP; Possi, Ana P. M. [UNESP; Cruz, Fabio C. [UNESP; Planeta, Cleopatra da Silva [UNESP

    2011-01-01

    Caffeine is the psychostimulant drug most consumed in the world. This drug is present in food, beverages and medicines marketed for individuals of all ages. In spite of this, caffeine effects on adolescents are poorly understood. The aim of this study was to evaluate the differences on caffeine-induced locomotor stimulant or depressant effects in adolescent and adult rats. Adolescent (37-40 days old) or adult (70-74 days old) Wistar rats were tested for stimulant and depressant caffeine effec...

  4. Cocaine-induced locomotor sensitization in rats correlates with nucleus accumbens activity on manganese-enhanced MRI.

    Science.gov (United States)

    Perrine, Shane A; Ghoddoussi, Farhad; Desai, Kirtan; Kohler, Robert J; Eapen, Ajay T; Lisieski, Michael J; Angoa-Perez, Mariana; Kuhn, Donald M; Bosse, Kelly E; Conti, Alana C; Bissig, David; Berkowitz, Bruce A

    2015-11-01

    A long-standing goal of substance abuse research has been to link drug-induced behavioral outcomes with the activity of specific brain regions to understand the neurobiology of addiction behaviors and to search for drug-able targets. Here, we tested the hypothesis that cocaine produces locomotor (behavioral) sensitization that correlates with increased calcium channel-mediated neuroactivity in brain regions linked with drug addiction, such as the nucleus accumbens (NAC), anterior striatum (AST) and hippocampus, as measured using manganese-enhanced MRI (MEMRI). Rats were treated with cocaine for 5 days, followed by a 2-day drug-free period. The following day, locomotor sensitization was quantified as a metric of cocaine-induced neuroplasticity in the presence of manganese. Immediately following behavioral testing, rats were examined for changes in calcium channel-mediated neuronal activity in the NAC, AST, hippocampus and temporalis muscle, which was associated with behavioral sensitization using MEMRI. Cocaine significantly increased locomotor activity and produced behavioral sensitization compared with saline treatment of control rats. A significant increase in MEMRI signal intensity was determined in the NAC, but not AST or hippocampus, of cocaine-treated rats compared with saline-treated control rats. Cocaine did not increase signal intensity in the temporalis muscle. Notably, in support of our hypothesis, behavior was significantly and positively correlated with MEMRI signal intensity in the NAC. As neuronal uptake of manganese is regulated by calcium channels, these results indicate that MEMRI is a powerful research tool to study neuronal activity in freely behaving animals and to guide new calcium channel-based therapies for the treatment of cocaine abuse and dependence. Copyright © 2015 John Wiley & Sons, Ltd.

  5. Ovariectomy influences the circadian rhythm of locomotor activity and the photic phase shifts in the volcano mouse.

    Science.gov (United States)

    Juárez-Tapia, Cinthia; Miranda-Anaya, Manuel

    2017-12-01

    Recently, the relationship between the circadian system and female reproduction has been of great interest; ovarian hormones can modify the amount and distribution of daily activity differently in rodent species. The volcano mouse Neotomodon alstoni is a species in which it is possible to study the circadian rhythm of locomotion, and it offers comparative information about the influence of ovaries on the circadian system. In this study, we used infrared crossings to compare free movement in intact and sham-operated or ovariectomized mice. We analyzed behavioral and endocrine changes related to the estrous cycle and locomotor circadian rhythm in free-running mice and photic phase shifting. Evidence shows that intact mice present a scalloped pattern of daily activity during the estrous cycle. In constant darkness, the ovariectomy reduces the total amount of activity, shortens the free-running circadian period of locomotion and increases photic phase shifts during the early subjective night. During entrainment, the ovariectomized mice increased the amplitude of total activity during the scotophase, and delay the time of activity onset. These results suggest that ovarian hormones in N. alstoni modulate the circadian rhythm of locomotor activity in a species-specific manner. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Gender-specific alteration of energy balance and circadian locomotor activity in the Crtc1 knockout mouse model of depression

    KAUST Repository

    Rossetti, Clara

    2017-12-06

    Obesity and depression are major public health concerns, and there is increasing evidence that they share etiological mechanisms. CREB-regulated transcription coactivator 1 (CRTC1) participates in neurobiological pathways involved in both mood and energy balance regulation. Crtc1 -/- mice rapidly develop a depressive-like and obese phenotype in early adulthood, and are therefore a relevant animal model to explore possible common mechanisms underlying mood disorders and obesity. Here, the obese phenotype of male and female Crtc1 -/- mice was further characterized by investigating CRTC1\\'s role in the homeostatic and hedonic regulation of food intake, as well as its influence on daily locomotor activity. Crtc1 -/- mice showed a strong gender difference in the homeostatic regulation of energy balance. Mutant males were hyperphagic and rapidly developed obesity on normal chow diet, whereas Crtc1 -/- females exhibited mild late-onset obesity without hyperphagia. Overeating of mutant males was accompanied by alterations in the expression of several orexigenic and anorexigenic hypothalamic genes, thus confirming a key role of CRTC1 in the central regulation of food intake. No alteration in preference and conditioned response for saccharine was observed in Crtc1 -/- mice, suggesting that mutant males\\' hyperphagia was not due to an altered hedonic regulation of food intake. Intriguingly, mutant males exhibited a hyperphagic behavior only during the resting (diurnal) phase of the light cycle. This abnormal feeding behavior was associated with a higher diurnal locomotor activity indicating that the lack of CRTC1 may affect circadian rhythmicity. Collectively, these findings highlight the male-specific involvement of CRTC1 in the central control of energy balance and circadian locomotor activity.

  7. Impairment of locomotor activity induced by the novel N-acylhydrazone derivatives LASSBio-785 and LASSBio-786 in mice

    Directory of Open Access Journals (Sweden)

    G.A.P. Silva

    Full Text Available The N-acylhydrazone (NAH analogues N-methyl 2-thienylidene 3,4-benzoylhydrazine (LASSBio-785 and N-benzyl 2-thienylidene 3,4-benzoylhydrazine (LASSBio-786 were prepared from 2-thienylidene 3,4-methylenedioxybenzoylhydrazine (LASSBio-294. The ability of LASSBio-785 and LASSBio-786 to decrease central nervous system activity was investigated in male Swiss mice. LASSBio-785 or LASSBio-786 (30 mg/kg, ip reduced locomotor activity from 209 ± 26 (control to 140 ± 18 (P < 0.05 or 146 ± 15 crossings/min (P < 0.05, respectively. LASSBio-785 (15 or 30 mg/kg, iv also reduced locomotor activity from 200 ± 15 to 116 ± 29 (P < 0.05 or 60 ± 16 crossings/min (P < 0.01, respectively. Likewise, LASSBio-786 (15 or 30 mg/kg, iv reduced locomotor activity from 200 ± 15 to 127 ± 10 (P < 0.01 or 96 ± 14 crossings/min (P < 0.01, respectively. Pretreatment with flumazenil (20 mg/kg, ip prevented the locomotor impairment induced by NAH analogues (15 mg/kg, iv, providing evidence that the benzodiazepine (BDZ receptor is involved. This finding was supported by the structural similarity of NAH analogues to midazolam. However, LASSBio-785 showed weak binding to the BDZ receptor. LASSBio-785 or LASSBio-786 (30 mg/kg, ip, n = 10 increased pentobarbital-induced sleeping time from 42 ± 5 (DMSO to 66 ± 6 (P < 0.05 or 75 ± 4 min (P < 0.05, respectively. The dose required to achieve 50% hypnosis (HD50 following iv injection of LASSBio-785 or LASSBio-786 was 15.8 or 9.5 mg/kg, respectively. These data suggest that both NAH analogues might be useful for the development of new neuroactive drugs for the treatment of insomnia or for use in conjunction with general anesthesia.

  8. Divergent selection on home pen locomotor activity in a chicken model: Selection program, genetic parameters and direct response on activity and body weight.

    Directory of Open Access Journals (Sweden)

    Joergen B Kjaer

    Full Text Available General locomotor activity (GLA in poultry has attracted attention, as it negatively influences production costs (energy expenditure and feed consumption and welfare parameters (bone strength, litter quality, feather pecking and cannibalism. Laying hen lines diverging in the average level of spontaneous locomotor activity in the home pen were developed by genetic selection using the founder New Hampshire line. Activity was recorded using RFID technology at around five weeks of age during four to five days in the home pen. After initial phenotyping, the least active birds were selected for the low activity line and the most active for the high activity line, with no gene transfer between lines. In each of six generations, approximately ten sires were mated to twenty dams producing 158 to 334 offspring per line per generation. The response to selection was rapid and of a considerable magnitude. In sixth generation, the level of GLA was approximately halved in the low and doubled in the high line compared to the control (7.2, 14.9 and 28.7 recordings/h. Estimated heritability of locomotor activity in the low and high line was 0.38 and 0.33, respectively. Males, in general, were more active than females. High line birds were significantly heavier than low line birds. In fourth, fifth, and sixth generation, low as well as high line birds were lighter than control line birds. This selection experiment demonstrates variation in heritability for GLA and, as a result, genetically diverged lines have been developed. These lines can be used as models for further studies of underlying physiological, neural and molecular genetic mechanisms of spontaneous locomotor activity.

  9. Effects of insemination and blood-feeding on locomotor activity of Aedes albopictus and Aedes aegypti (Diptera: Culicidae) females under laboratory conditions.

    Science.gov (United States)

    Lima-Camara, Tamara Nunes; Lima, José Bento Pereira; Bruno, Rafaela Vieira; Peixoto, Alexandre Afranio

    2014-07-02

    Dengue is an arbovirus disease transmitted by two Aedes mosquitoes: Ae. aegypti and Ae. albopictus. Virgin females of these two species generally show a bimodal and diurnal pattern of activity, with early morning and late afternoon peaks. Although some studies on the flight activity of virgin, inseminated and blood-fed Ae. aegypti females have been carried out under laboratory conditions, little is known about the effects of such physiological states on the locomotor activity of Ae. albopictus and Ae. aegypti females. The aim of this study was to analyze, under laboratory conditions, the effects of insemination and blood-feeding on the locomotor activity of Ae. albopictus and Ae. aegypti females under LD 12:12, at 25°C. Both Ae. albopictus and Ae. aegypti females were obtained from established laboratory colonies. Control groups were represented by virgin/unfed Ae. albopictus and Ae. aegypti females. Experiments were conducted under laboratory conditions, using an activity monitor that registers individual activity every thirty minutes. Virgin/unfed Ae. albopictus and Ae. aegypti females showed a diurnal and bimodal pattern of locomotor activity, with peaks at early morning and late afternoon. Insemination and blood-feeding significantly decreased the locomotor activity of Ae. aegypti females, but inseminated/blood-fed Ae. aegypti and Ae. albopictus females showed a similar significant decrease on the locomotor activity compared to virgin/unfed females. This study is the first demonstration of the effects of insemination and blood-feeding on the locomotor activity of Ae. albopictus and Ae. aegypti females under artificial conditions. Data suggest that Ae. albopictus and Ae. aegypti females respond in different ways to physiological status changes and such divergence between these two dengue vectors, associated with several ecological differences, could be related to the greater dengue vectorial capacity of Ae. aegypti in Americas in comparison to Ae. albopictus.

  10. Attenuation of cocaine-induced locomotor activity in male and female mice by active immunization.

    Science.gov (United States)

    Kosten, Therese A; Shen, Xiaoyun Y; Kinsey, Berma M; Kosten, Thomas R; Orson, Frank M

    2014-01-01

    Immunotherapy for drug addiction is being investigated in several laboratories but most studies are conducted in animals of one sex. Yet, women show heightened immune responses and are more likely to develop autoimmune diseases than men. The purpose of this study was to compare the effects of an active anti-cocaine vaccine, succinyl-norcocaine conjugated to keyhole limpet hemocyanin, for its ability to elicit antibodies and alter cocaine-induced ambulatory activity in male versus female mice. Male and female BALB/c mice were vaccinated (n = 44) or served as non-vaccinated controls (n = 34). Three weeks after initial vaccination, a booster was given. Ambulatory activity induced by cocaine (20 mg/kg) was assessed at 7 weeks and plasma obtained at 8 weeks to assess antibody levels. High antibody titers were produced in mice of both sexes. The vaccine reduced ambulatory activity cocaine-induced but this effect was greater in female compared to male mice. The efficacy of this anti-cocaine vaccine is demonstrated in mice of both sexes but its functional consequences are greater in females than males. Results point to the importance of testing animals of both sexes in studies of immunotherapies for addiction. © American Academy of Addiction Psychiatry.

  11. Cognitive deficits and decreased locomotor activity induced by single-walled carbon nanotubes and neuroprotective effects of ascorbic acid

    Science.gov (United States)

    Liu, Xudong; Zhang, Yuchao; Li, Jinquan; Wang, Dong; Wu, Yang; Li, Yan; Lu, Zhisong; Yu, Samuel CT; Li, Rui; Yang, Xu

    2014-01-01

    Single-walled carbon nanotubes (SWCNTs) have shown increasing promise in the field of biomedicine, especially in applications related to the nervous system. However, there are limited studies available on the neurotoxicity of SWCNTs used in vivo. In this study, neurobehavioral changes caused by SWCNTs in mice and oxidative stress were investigated. The results of ethological analysis (Morris water maze and open-field test), brain histopathological examination, and assessments of oxidative stress (reactive oxygen species [ROS], malondialdehyde [MDA], and glutathione [GSH]), inflammation (nuclear factor κB, tumor necrosis factor α, interleukin-1β), and apoptosis (cysteine-aspartic acid protease 3) in brains showed that 6.25 and 12.50 mg/kg/day SWCNTs in mice could induce cognitive deficits and decreased locomotor activity, brain histopathological alterations, and increased levels of oxidative stress, inflammation, and apoptosis in mouse brains; however, 3.125 mg/kg/day SWCNTs had zero or minor adverse effects in mice, and these effects were blocked by concurrent administration of ascorbic acid. Down-regulation of oxidative stress, inflammation, and apoptosis were proposed to explain the neuroprotective effects of ascorbic acid. This work suggests SWCNTs could induce cognitive deficits and decreased locomotor activity, and provides a strategy to avoid the adverse effects. PMID:24596461

  12. Locomotor activation by theacrine, a purine alkaloid structurally similar to caffeine: involvement of adenosine and dopamine receptors.

    Science.gov (United States)

    Feduccia, Allison A; Wang, Yuanyuan; Simms, Jeffrey A; Yi, Henry Y; Li, Rui; Bjeldanes, Leonard; Ye, Chuangxing; Bartlett, Selena E

    2012-08-01

    Purine compounds, such as caffeine, have many health-promoting properties and have proven to be beneficial in treating a number of different conditions. Theacrine, a purine alkaloid structurally similar to caffeine and abundantly present in Camellia kucha, has recently become of interest as a potential therapeutic compound. In the present study, theacrine was tested using a rodent behavioral model to investigate the effects of the drug on locomotor activity. Long Evans rats were injected with theacrine (24 or 48 mg/kg, i.p.) and activity levels were measured. Results showed that the highest dose of theacrine (48 mg/kg, i.p.) significantly increased locomotor activity compared to control animals and activity remained elevated throughout the duration of the session. To test for the involvement of adenosine receptors underlying theacrine's motor-activating properties, rats were administered a cocktail of the adenosine A₁ agonist, N⁶-cyclopentyladenosine (CPA; 0.1 mg/kg, i.p.) and A(2A) receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS-21680; 0.2 mg/kg, i.p.). Pre-treatment with theacrine significantly attenuated the motor depression induced by the adenosine receptor agonists, indicating that theacrine is likely acting as an adenosine receptor antagonist. Next, we examined the role of DA D₁ and D₂ receptor antagonism on theacrine-induced hyperlocomotion. Both antagonists, D₁R SCH23390 (0.1 or 0.05 mg/kg, i.p.) and D₂R eticlopride (0.1 mg/kg, i.p.), significantly reduced theacrine-stimulated activity indicating that this behavioral response, at least in part, is mediated by DA receptors. In order to investigate the brain region where theacrine may be acting, the drug (10 or 20 μg) was infused bilaterally into nucleus accumbens (NAc). Theacrine enhanced activity levels in a dose-dependent manner, implicating a role of the NAc in modulating theacrine's effects on locomotion. In addition, theacrine did not induce locomotor

  13. Locomotor activity, enjoyment and perceived exertion from 7v7 football for patients with Parkinson’s disease

    DEFF Research Database (Denmark)

    Møller, Trine Kjeldgaard Tang; Madsen, Mads; Frederiksen, Jakob

    Background: The level of daily physical activity decrease with disease severity in patients with Parkinson’s disease. Furthermore, inactivity is associated with greater disabilities in daily life and secondary complications. Participation in recreational football, organized as small-sided games......, on a regularly basis show benefits in the health profile and physical capacity in untrained adult men, and improves both cardiovascular and metabolic fitness. Purpose: The purpose of this study is to describe locomotor activities, enjoyment and perceived exertion during football training for men with Parkinson...... on a 40x40 m artificial turf football pitch with 1.5x3 m goals. After each activity perceived exertion for lower limbs and total body individually was rated on a visual analogue scale (0-10). After the whole session the participants filled out a PACES questionnaire to rate enjoyment of the session. Height...

  14. Effects of simultaneous exposure to stress and nicotine on nicotine-induced locomotor activation in adolescent and adult rats

    Energy Technology Data Exchange (ETDEWEB)

    Zago, A. [Laboratório de Farmacologia, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, Araraquara, SP (Brazil); Leão, R.M.; Carneiro-de-Oliveira, P.E. [Laboratório de Farmacologia, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, Araraquara, SP (Brazil); Programa Interinstitucional de Pós-Graduação em Ciências Fisiológicas, Universidade Federal de São Carlos/Universidade Estadual de São Paulo, Araraquara, SP (Brazil); Marin, M.T.; Cruz, F.C. [Laboratório de Farmacologia, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, Araraquara, SP (Brazil); Planeta, C.S. [Laboratório de Farmacologia, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, Araraquara, SP (Brazil); Programa Interinstitucional de Pós-Graduação em Ciências Fisiológicas, Universidade Federal de São Carlos/Universidade Estadual de São Paulo, Araraquara, SP (Brazil)

    2011-11-18

    Preclinical studies have shown that repeated stress experiences can result in an increase in the locomotor response to the subsequent administration of drugs of abuse, a phenomenon that has been termed behavioral cross-sensitization. Behavioral sensitization reflects neuroadaptive processes associated with drug addiction and drug-induced psychosis. Although crosssensitization between stress- and drug-induced locomotor activity has been clearly demonstrated in adult rats, few studies have evaluated this phenomenon in adolescent rats. In the present study, we determined if the simultaneous exposure to stress and nicotine was capable of inducing behavioral sensitization to nicotine in adolescent and adult rats. To this end, adolescent (postnatal day (P) 28-37) and adult (P60-67) rats received nicotine (0.4 mg/kg, sc) or saline (0.9% NaCl, sc) and were immediately subjected to restraint stress for 2 h once a day for 7 days. The control group for stress was undisturbed following nicotine or saline injections. Three days after the last exposure to stress and nicotine, rats were challenged with a single dose of nicotine (0.4 mg/kg, sc) or saline and nicotine-induced locomotion was then recorded for 30 min. In adolescent rats, nicotine caused behavioral sensitization only in animals that were simultaneously exposed to stress, while in adult rats nicotine promoted sensitization independently of stress exposure. These findings demonstrate that adolescent rats are more vulnerable to the effects of stress on behavioral sensitization to nicotine than adult rats.

  15. Effects of simultaneous exposure to stress and nicotine on nicotine-induced locomotor activation in adolescent and adult rats

    International Nuclear Information System (INIS)

    Zago, A.; Leão, R.M.; Carneiro-de-Oliveira, P.E.; Marin, M.T.; Cruz, F.C.; Planeta, C.S.

    2011-01-01

    Preclinical studies have shown that repeated stress experiences can result in an increase in the locomotor response to the subsequent administration of drugs of abuse, a phenomenon that has been termed behavioral cross-sensitization. Behavioral sensitization reflects neuroadaptive processes associated with drug addiction and drug-induced psychosis. Although crosssensitization between stress- and drug-induced locomotor activity has been clearly demonstrated in adult rats, few studies have evaluated this phenomenon in adolescent rats. In the present study, we determined if the simultaneous exposure to stress and nicotine was capable of inducing behavioral sensitization to nicotine in adolescent and adult rats. To this end, adolescent (postnatal day (P) 28-37) and adult (P60-67) rats received nicotine (0.4 mg/kg, sc) or saline (0.9% NaCl, sc) and were immediately subjected to restraint stress for 2 h once a day for 7 days. The control group for stress was undisturbed following nicotine or saline injections. Three days after the last exposure to stress and nicotine, rats were challenged with a single dose of nicotine (0.4 mg/kg, sc) or saline and nicotine-induced locomotion was then recorded for 30 min. In adolescent rats, nicotine caused behavioral sensitization only in animals that were simultaneously exposed to stress, while in adult rats nicotine promoted sensitization independently of stress exposure. These findings demonstrate that adolescent rats are more vulnerable to the effects of stress on behavioral sensitization to nicotine than adult rats

  16. Effect of subacute poisoning with bifenthrin on locomotor activity, memory retention, haematological, biochemical and histopathological parameters in mice.

    Science.gov (United States)

    Nieradko-Iwanicka, B; Borzecki, A; Jodlowska-Jedrych, B

    2015-02-01

    Bifenthrin (BIF) is a pyrethroid (PYR) insecticide. The target point for PYR's toxic action are voltage sensitive sodium channels in the central nervous system (CNS). Intoxication with PYRs results in motor activity impairment and death in insects. Although PYRs are considered to be safe for mammals, there were numerous cases of pyrethroid poisoning in humans, animals and pets described. The general population is chronically exposed to PYRs via grain products, dust and indoor air. Therefore new questions arise: whether PYRs act in a dose-additive fashion in the course of subacute poisoning, are there other target organs (but brain) for BIF and if there is one common mechanism of its' toxic action in different organs. The objective of this work was to characterize the effect of BIF at the doses of 4 or 8 mg/kg injected intraperitoneally (i.p.) daily for 28 consecutive days on memory and motor activity, hematological, biochemical and histopathological parameters in mice. BIF at the doses of 8 mg/kg or 4 mg/kg of body mass was administered i.p. daily to the mice for 28 consecutive days. Motor function was measured on day 1, 7, 14 and 28 and memory retention was tested in a passive avoidance task on day 2, 7, 14 and 28. BIF significantly impaired memory retention on day 2. BIF decreased locomotor activity at every stage of the experiment in a single dose depending manner. No behavioral cumulative effect was observed. Subacute poisoning with the higher dose of BIF caused anaemia, elevated white blood cell count (WBC), elevated alanine transaminase (ALT), superoxide dismuthase (SOD), and decreased glutathione peroxidase (GPx) activity. Lymphocyte infiltrates were visualized in the livers. subacute poisoning with BIF decreases locomotor activity in a single dose proportionate manner. BIF damages also the liver and alters blood morphology. The possible common mechanism of these effects can be oxidative stress.

  17. Effect of glycine site/NMDA receptor antagonist MRZ2/576 on the conditioned place preference and locomotor activity induced by morphine in mice*

    OpenAIRE

    Zhu, Yong-ping; Long, Zai-hao; Zheng, Ming-lan; Binsack, Ralf

    2006-01-01

    Objective: To study the effect of glycine site/NMDA (N-methyl-D-aspartate) receptor antagonist MRZ2/576 on the conditioned place preference (CPP) and locomotor activity induced by morphine in mice. Methods: Different doses (1.25, 2.5 and 5 mg/kg, i.p.) of MRZ2/576 were used to evaluate the effect of MRZ2/576 on the acquisition and expression of CPP induced by morphine (5 mg/kg) in mice. In addition, we examined the locomotor activity of mice in conditioning and testing phase of CPP paradigm. ...

  18. A high-fat diet rich in corn oil reduces spontaneous locomotor activity and induces insulin resistance in mice.

    Science.gov (United States)

    Wong, Chi Kin; Botta, Amy; Pither, Jason; Dai, Chuanbin; Gibson, William T; Ghosh, Sanjoy

    2015-04-01

    Over the last few decades, polyunsaturated fatty acid (PUFA), especially n-6 PUFA, and monounsaturated fatty acid content in 'Western diets' has increased manyfold. Such a dietary shift also parallels rising sedentary behavior and diabetes in the Western world. We queried if a shift in dietary fats could be linked to physical inactivity and insulin insensitivity in mice. Eight-week old female C57/Bl6 mice were fed either high-fat (HF) diets [40% energy corn oil (CO) or isocaloric olive oil (OO) diets] or chow (n=10/group) for 6 weeks, followed by estimation of spontaneous locomotor activity, body composition and in vivo metabolic outcomes. Although lean mass and resting energy expenditure stayed similar in both OO- and CO-fed mice, only CO-fed mice demonstrated reduced spontaneous locomotor activity. Such depressed activity in CO-fed mice was accompanied by a lower respiratory ratio, hyperinsulinemia and impaired glucose disposal following intraperitoneal glucose tolerance and insulin tolerance tests compared to OO-fed mice. Unlike the liver, where both HF diets increased expression of fat oxidation genes like PPARs, the skeletal muscle of CO-fed mice failed to up-regulate such genes, thereby supporting the metabolic insufficiencies observed in these mice. In summary, this study demonstrates a specific contribution of n-6 PUFA-rich oils like CO to the loss of spontaneous physical activity and insulin sensitivity in mice. If these data hold true for humans, this study could provide a novel link between recent increases in dietary n-6 PUFA to sedentary behavior and the development of insulin resistance in the Western world. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Greater ethanol-induced locomotor activation in DBA/2J versus C57BL/6J mice is not predicted by presynaptic striatal dopamine dynamics.

    Directory of Open Access Journals (Sweden)

    Jamie H Rose

    Full Text Available A large body of research has aimed to determine the neurochemical factors driving differential sensitivity to ethanol between individuals in an attempt to find predictors of ethanol abuse vulnerability. Here we find that the locomotor activating effects of ethanol are markedly greater in DBA/2J compared to C57BL/6J mice, although it is unclear as to what neurochemical differences between strains mediate this behavior. Dopamine elevations in the nucleus accumbens and caudate-putamen regulate locomotor behavior for most drugs, including ethanol; thus, we aimed to determine if differences in these regions predict strain differences in ethanol-induced locomotor activity. Previous studies suggest that ethanol interacts with the dopamine transporter, potentially mediating its locomotor activating effects; however, we found that ethanol had no effects on dopamine uptake in either strain. Ex vivo voltammetry allows for the determination of ethanol effects on presynaptic dopamine terminals, independent of drug-induced changes in firing rates of afferent inputs from either dopamine neurons or other neurotransmitter systems. However, differences in striatal dopamine dynamics did not predict the locomotor-activating effects of ethanol, since the inhibitory effects of ethanol on dopamine release were similar between strains. There were differences in presynaptic dopamine function between strains, with faster dopamine clearance in the caudate-putamen of DBA/2J mice; however, it is unclear how this difference relates to locomotor behavior. Because of the role of the dopamine system in reinforcement and reward learning, differences in dopamine signaling between the strains could have implications for addiction-related behaviors that extend beyond ethanol effects in the striatum.

  20. Application of the Copenhagen Soccer Test in high-level women players - locomotor activities, physiological response and sprint performance.

    Science.gov (United States)

    Bendiksen, Mads; Pettersen, Svein Arne; Ingebrigtsen, Jørgen; Randers, Morten B; Brito, João; Mohr, Magni; Bangsbo, Jens; Krustrup, Peter

    2013-12-01

    We evaluated the physiological response, sprint performance and technical ability in various phases of the Copenhagen Soccer Test for Women (CSTw) and investigated whether the locomotor activities of the CSTw were comparable to competitive match-play (CM). Physiological measurements and physical/technical assessments were performed during CSTw for eleven Norwegian high-level women soccer players. The activity pattern during CSTw and CM was monitored using the ZXY tracking system. No differences were observed between CSTw and CM with regards to total distance covered (10093±94 and 9674±191m), high intensity running (1278±67 and 1193±115m) or sprinting (422±55 and 372±46m) (p>.05). During CSTw, average HR was 85±2%HRmax with 35±2% playing time >90%HRmax. Blood lactate increased (p<.05) from 1.4±0.3mM at rest to an average of 4.7±0.5mM during CSTw, with no changes during the test. Blood glucose was 5.4±0.3mM at rest and remained unaltered during CSTw. Sprint performance (2×20m) decreased (p<.05) by 3% during CSTw (8.19±0.06-8.47±0.10s). In conclusion, the locomotor activities during CSTw were comparable to that of high-level competitive match-play. The physiological demands of the CSTw were high, with no changes in heart rate, blood lactate or technical performance during the test, but a lowered sprint performance towards the end of the test. Copyright © 2013 Elsevier B.V. All rights reserved.

  1. l-5-hydroxytryptophan resets the circadian locomotor activity rhythm of the nocturnal Indian pygmy field mouse, Mus terricolor

    Science.gov (United States)

    Basu, Priyoneel; Singaravel, Muniyandi; Haldar, Chandana

    2012-03-01

    We report that l-5-hydroxytryptophan (5-HTP), a serotonin precursor, resets the overt circadian rhythm in the Indian pygmy field mouse, Mus terricolor, in a phase- and dose-dependent manner. We used wheel running to assess phase shifts in the free-running locomotor activity rhythm. Following entrainment to a 12:12 h light-dark cycle, 5-HTP (100 mg/kg in saline) was intraperitoneally administered in complete darkness at circadian time (CT)s 0, 3, 6, 9, 12, 15, 18, and 21, and the ensuing phase shifts in the locomotor activity rhythm were calculated. The results show that 5-HTP differentially shifts the phase of the rhythm, causing phase advances from CT 0 to CT 12 and phase delays from CT 12 to CT 21. Maximum advance phase shift was at CT 6 (1.18 ± 0.37 h) and maximum delay was at CT 18 (-2.36 ± 0.56 h). No extended dead zone is apparent. Vehicle (saline) at any CT did not evoke a significant phase shift. Investigations with different doses (10, 50, 100, and 200 mg/kg) of 5-HTP revealed that the phase resetting effect is dose-dependent. The shape of the phase-response curve (PRC) has a strong similarity to PRCs obtained using some serotonergic agents. There was no significant increase in wheel-running activity after 5-HTP injection, ruling out behavioral arousal-dependent shifts. This suggests that this phase resetting does not completely depend on feedback of the overt rhythmic behavior on the circadian clock. A mechanistic explanation of these shifts is currently lacking.

  2. Microbial enrichment to enhance the disease suppressive activity of compost

    NARCIS (Netherlands)

    Postma, J.; Montenari, M.; Boogert, van den P.H.J.F.

    2003-01-01

    Compost amended soil has been found to be suppressive against plant diseases in various cropping systems. The level and reproducibility of disease suppressive properties of compost might be increased by the addition of antagonists. In the present study, the establishment and suppressive activity of

  3. Effects of pinealectomy on the neuroendocrine reproductive system and locomotor activity in male European sea bass, Dicentrarchus labrax.

    Science.gov (United States)

    Cowan, Mairi; Paullada-Salmerón, José A; López-Olmeda, José Fernando; Sánchez-Vázquez, Francisco Javier; Muñoz-Cueto, José A

    2017-05-01

    The seasonally changing photoperiod controls the timing of reproduction in most fish species, however, the transduction of this photoperiodic information to the reproductive axis is still unclear. This study explored the potential role of two candidate neuropeptide systems, gonadotropin-inhibitory hormone (Gnih) and kisspeptin, as mediators between the pineal organ (a principle transducer of photoperiodic information) and reproductive axis in male European sea bass, Dicentrarchus labrax. Two seven-day experiments of pinealectomy (Px) were performed, in March (end of reproductive season) and August (resting season). Effects of Px and season on the brain expression of gnih (sbgnih) and its receptor (sbgnihr), kisspeptins (kiss1, kiss2) and their receptors (kissr2, kissr3) and gonadotropin-releasing hormone (gnrh1, gnrh2, gnrh3) and the main brain receptor (gnrhr-II-2b) genes, plasma melatonin levels and locomotor activity rhythms were examined. Results showed that Px reduced night-time plasma melatonin levels. Gene expression analyses demonstrated a sensitivity of the Gnih system to Px in March, with a reduction in sbgnih in the mid-hindbrain, a region with bilateral connections to the pineal organ. In August, kiss2 levels increased in Px animals but not in controls. Significant differences in expression were observed for diencephalic sbgnih, sbgnihr, kissr3 and tegmental gnrh2 between seasons. Recordings of locomotor activity following surgery revealed a change from light-synchronised to free-running rhythmic behavior. Altogether, the Gnih and Kiss2 sensitivity to Px and seasonal differences observed for Gnih and its receptor, Gnrh2, and the receptor for Kiss2 (Kissr3), suggested they could be mediators involved in the relay between environment and seasonal reproduction. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Effects of paraxanthine and caffeine on sleep, locomotor activity, and body temperature in orexin/ataxin-3 transgenic narcoleptic mice.

    Science.gov (United States)

    Okuro, Masashi; Fujiki, Nobuhiro; Kotorii, Nozomu; Ishimaru, Yuji; Sokoloff, Pierre; Nishino, Seiji

    2010-07-01

    Caffeine, an adenosine A1 and A2a receptor antagonist, is a widely consumed stimulant and also used for the treatment of hypersomnia; however, the wake-promoting potency of caffeine is often not strong enough, and high doses may induce side effects. Caffeine is metabolized to paraxanthine, theobromine, and theophylline. Paraxanthine is a central nervous stimulant and exhibits higher potency at A1 and A2 receptors, but has lower toxicity and lesser anxiogenic effects than caffeine. We evaluated the wake-promoting efficacy of paraxanthine, caffeine, and a reference wake-promoting compound, modafinil, in a mice model of narcolepsy, a prototypical disease model of hypersomnia. Orexin/ataxin-3 transgenic (TG) and wild-type (WT) mice were subjected to oral administration (at ZT 2 and ZT14) of 3 doses of paraxanthine, caffeine, modafinil, or vehicle. Paraxanthine, caffeine, and modafinil significantly promoted wakefulness in both WT and narcoleptic TG mice and proportionally reduced NREM and REM sleep in both genotypes. The wake-promoting potency of 100 mg/kg p.o. of paraxanthine during the light period administration roughly corresponds to that of 200 mg/kg p.o. of modafinil. The wake-promoting potency of paraxanthine is greater and longer lasting than that of the equimolar concentration of caffeine, when the drugs were administered during the light period. The wake-promotion by paraxanthine, caffeine, and modafinil are associated with an increase in locomotor activity and body temperature. However, the higher doses of caffeine and modafinil, but not paraxanthine, induced hypothermia and reduced locomotor activity, thereby confirming the lower toxicity of paraxanthine. Behavioral evaluations of anxiety levels in WT mice revealed that paraxanthine induced less anxiety than caffeine did. Because it is also reported to provide neuroprotection, paraxanthine may be a better wake-promoting agent for hypersomnia associated with neurodegenerative diseases.

  5. Orbital bleeding in rats while under diethylether anaesthesia does not influence telemetrically determined heart rate, body temperature, locomotor and eating activity when compared with anaesthesia alone

    NARCIS (Netherlands)

    vanHerck, H; DeBoer, SF; Hesp, APM; VanLith, HA; Baumans, [No Value; Beynen, AC; Herck, H. van; Lith, H.A. van

    The question addressed was whether orbital bleeding in rats, while under diethylether anaesthesia, affects their locomotor activity, body core temperature, heart rate rhythm and eating pattern. Roman High Avoidance (RHA) and Roman Low Avoidance (RLA) rats were used to enhance generalization of the

  6. An enriched environment reduces the stress level and locomotor activity induced by acute morphine treatment and by saline after chronic morphine treatment in mice.

    Science.gov (United States)

    Xu, Jia; Sun, Jinling; Xue, Zhaoxia; Li, Xinwang

    2014-06-18

    This study investigated the relationships among an enriched environment, stress levels, and drug addiction. Mice were divided randomly into four treatment groups (n=12 each): enriched environment without restraint stress (EN), standard environment without restraint stress (SN), enriched environment with restraint stress (ES), and standard environment with restraint stress (SS). Mice were reared in the respective environment for 45 days. Then, the ES and SS groups were subjected to restraint stress daily (2 h/day) for 14 days, whereas the EN and SN groups were not subjected to restraint stress during this stage. The stress levels of all mice were tested in the elevated plus maze immediately after exposure to restraint stress. After the 2-week stress testing period, mice were administered acute or chronic morphine (5 mg/kg) treatment for 7 days. Then, after a 7-day withdrawal period, the mice were injected with saline (1 ml/kg) or morphine (5 mg/kg) daily for 2 days to observe locomotor activity. The results indicated that the enriched environment reduced the stress and locomotor activity induced by acute morphine administration or saline after chronic morphine treatment. However, the enriched environment did not significantly inhibit locomotor activity induced by morphine challenge. In addition, the stress level did not mediate the effect of the enriched environment on drug-induced locomotor activity after acute or chronic morphine treatment.

  7. Supplementation of Spirulina (Arthrospira platensis) Improves Lifespan and Locomotor Activity in Paraquat-Sensitive DJ-1βΔ93Flies, a Parkinson's Disease Model in Drosophila melanogaster.

    Science.gov (United States)

    Kumar, Ajay; Christian, Pearl K; Panchal, Komal; Guruprasad, B R; Tiwari, Anand K

    2017-09-03

    Spirulina (Arthrospira platensis) is a cyanobacterium (blue-green alga) consumed by humans and other animals because of its nutritional values and pharmacological properties. Apart from high protein contents, it also contains high levels of antioxidant and anti-inflammatory compounds, such as carotenoids, β-carotene, phycocyanin, and phycocyanobilin, indicating its possible pharmaco-therapeutic utility. In the present study using DJ-1β Δ93 flies, a Parkinson's disease model in Drosophila, we have demonstrated the therapeutic effect of spirulina and its active component C-phycocyanin (C-PC) in the improvement of lifespan and locomotor behavior. Our findings indicate that dietary supplementation of spirulina significantly improves the lifespan and locomotor activity of paraquat-fed DJ-1β Δ93 flies. Furthermore, supplementation of spirulina and C-PC individually and independently reduced the cellular stress marked by deregulating the expression of heat shock protein 70 and Jun-N-terminal kinase signaling in DJ-1β Δ93 flies. A significant decrease in superoxide dismutase and catalase activities in spirulina-fed DJ-1β Δ93 flies tends to indicate the involvement of antioxidant properties associated with spirulina in the modulation of stress-induced signaling and improvement in lifespan and locomotor activity in Drosophila DJ-1β Δ93 flies. Our results suggest that antioxidant boosting properties of spirulina can be used as a nutritional supplement for improving the lifespan and locomotor behavior in Parkinson's disease.

  8. Effects of simultaneous exposure to stress and nicotine on nicotine-induced locomotor activation in adolescent and adult rats

    Directory of Open Access Journals (Sweden)

    A. Zago

    2012-01-01

    Full Text Available Preclinical studies have shown that repeated stress experiences can result in an increase in the locomotor response to the subsequent administration of drugs of abuse, a phenomenon that has been termed behavioral cross-sensitization. Behavioral sensitization reflects neuroadaptive processes associated with drug addiction and drug-induced psychosis. Although cross-sensitization between stress- and drug-induced locomotor activity has been clearly demonstrated in adult rats, few studies have evaluated this phenomenon in adolescent rats. In the present study, we determined if the simultaneous exposure to stress and nicotine was capable of inducing behavioral sensitization to nicotine in adolescent and adult rats. To this end, adolescent (postnatal day (P 28-37 and adult (P60-67 rats received nicotine (0.4 mg/kg, sc or saline (0.9% NaCl, sc and were immediately subjected to restraint stress for 2 h once a day for 7 days. The control group for stress was undisturbed following nicotine or saline injections. Three days after the last exposure to stress and nicotine, rats were challenged with a single dose of nicotine (0.4 mg/kg, sc or saline and nicotine-induced locomotion was then recorded for 30 min. In adolescent rats, nicotine caused behavioral sensitization only in animals that were simultaneously exposed to stress, while in adult rats nicotine promoted sensitization independently of stress exposure. These findings demonstrate that adolescent rats are more vulnerable to the effects of stress on behavioral sensitization to nicotine than adult rats.

  9. [Diurnal rythm of locomotor activity in Admetus pumilio C. Koch (Arach., Amblypygi) from the neotropical rain forest. II].

    Science.gov (United States)

    Beck, L

    1972-03-01

    The locomotor activity of the exclusively dark-active species Admetus pumilio shows a bigeminal type of diurnal rhythm, modified by an interposed third peak of activity. In accordance with Aschoff's rule, the period length depends on light intensity and is shortened in DD. The phase-angle difference must be determined separately for each form of activity. The first movements at the resting place ("awakening") and departure from it are the most readily identifiable forms of activity. Awakening takes place earlier and earlier with decreasing light intensity, thus diverging from departure more and more.Differing degrees of activity in LL and LD of different intensities show that light stimulates or inhibits depending on its intensity. The turning point between the two effects lies between 10 -2 and 10 -3 lx. Below this limit differences in light intensity are not discerned, although LL is well discerned from LD.Diurnal temperature cycles with amplitudes up to 8° C are unable to synchronize the circadian rhythm of Admetus, but may have a strongly masking effect. Different levels of constant temperatures influence the phase-angle differences, which become increasingly positive with rising temperature. Activity also increases with temperature, but decreases in the extra-optimal range above approximately 30° C. The L-phase/D-phase ratio of activity shows a maximum at about 26° C.In Admetus the dependence of activity parameters upon light intensity is unidirectional and shows no optima. In contrast to the findings by Erkert (1967) is discussed that optima are only realized in dusk active animals and are lacking in day-active and night-active species.

  10. Drosophila male sex peptide inhibits siesta sleep and promotes locomotor activity in the post-mated female.

    Science.gov (United States)

    Isaac, R Elwyn; Li, Chenxi; Leedale, Amy E; Shirras, Alan D

    2010-01-07

    Quiescence, or a sleep-like state, is a common and important feature of the daily lives of animals from both invertebrate and vertebrate taxa, suggesting that sleep appeared early in animal evolution. Recently, Drosophila melanogaster has been shown to be a relevant and powerful model for the genetic analysis of sleep behaviour. The sleep architecture of D. melanogaster is sexually dimorphic, with females sleeping much less than males during day-time, presumably because reproductive success requires greater foraging activity by the female as well as the search for egg-laying sites. However, this loss of sleep and increase in locomotor activity will heighten the risk for the female from environmental and predator hazards. In this study, we show that virgin females can minimize this risk by behaving like males, with an extended afternoon 'siesta'. Copulation results in the female losing 70 per cent of day-time sleep and becoming more active. This behaviour lasts for at least 8 days after copulation and is abolished if the mating males lack sex peptide (SP), normally present in the seminal fluid. Our results suggest that SP is the molecular switch that promotes wakefulness in the post-mated female, a change of behaviour compatible with increased foraging and egg-laying activity. The stress resulting from SP-dependent sleep deprivation might be an important contribution to the toxic side-effects of male accessory gland products that are known to reduce lifespan in post-mated females.

  11. Day or night administration of ketamine and pentobarbital differentially affect circadian rhythms of pineal melatonin secretion and locomotor activity in rats.

    Science.gov (United States)

    Mihara, Takahiro; Kikuchi, Tatsuaki; Kamiya, Yoshinori; Koga, Motokazu; Uchimoto, Kazuhiro; Kurahashi, Kiyoyasu; Goto, Takahisa

    2012-10-01

    Surgery with general anesthesia disturbs circadian rhythms, which may lead to postoperative sleep disorders and delirium in patients. However, it is unclear how circadian rhythms are affected by different anesthetics administered at different times during the rest-activity cycle. We hypothesized that pentobarbital (an agonist at the γ-aminobutyric acid A receptors) and ketamine (an antagonist at the N-methyl-d-aspartate receptors) would have differential effects on circadian rhythms, and these effects would also be influenced by the time of their administration (the active versus resting phase). Rats were divided into 4 groups according to the anesthetic administered (pentobarbital or ketamine) and the timing of intraperitoneal administration (active/night phase or resting/day phase). Using online pineal microdialysis, we analyzed pineal melatonin secretion and locomotor activity rhythms in rats under a light/dark (12/12-hour) cycle for 5 days after anesthesia and microdialysis catheter implantation. The data were analyzed for rhythmicity by cosinor analysis. Ketamine administered during the resting phase produced 65- and 153-minute phase advances, respectively, in melatonin secretion and locomotor activity rhythms on the first day after anesthesia. In contrast, ketamine administered during the active phase produced 43- and 235-minute phase delays. Pentobarbital had no effect on the phase of either melatonin secretion or locomotor activity, irrespective of the timing of administration. When administered during the active phase, both anesthetics decreased the amplitude of melatonin secretion on the day after anesthesia; when administered during the resting phase, however, neither anesthetic affected the amplitude. The amplitude of locomotor activity decreased in all animals for 3 days after anesthesia. Ketamine has opposite phase-shifting effects on circadian rhythms according to the time of administration, whereas pentobarbital has no effect. Furthermore, both

  12. Organophosphate pesticides induce morphological abnormalities and decrease locomotor activity and heart rate in Danio rerio and Xenopus laevis.

    Science.gov (United States)

    Watson, Fiona L; Schmidt, Hayden; Turman, Zackery K; Hole, Natalie; Garcia, Hena; Gregg, Jonathan; Tilghman, Joseph; Fradinger, Erica A

    2014-06-01

    Organophosphate pesticides (OPs), a class of acetylcholinesterase inhibitors, are used widely in agriculture to reduce insect populations. Because of the conservation of acetylcholinesterase between invertebrates and vertebrates, OPs also can adversely affect nontarget species, such as aquatic and terrestrial animals. This study used uniform conditions to analyze the morphological and physiological effects caused by developmental exposure to 3 commonly used OPs-chlorpyrifos, dichlorvos, and diazinon-on 2 aquatic vertebrate species, Danio rerio (zebrafish) and Xenopus laevis. Survival, locomotor activity, heart rate, and gross anatomical abnormalities, including kyphosis and edema, were observed over a 5-d period in response to OP concentrations ranging from 0 µM to 1000 µM. Both zebrafish and Xenopus showed decreased survival for all 3 OPs at higher concentrations. However, Xenopus showed higher mortality than zebrafish at lower chlorpyrifos and dichlorvos concentrations. Both models showed a dose-dependent decrease in heart rate and free-swimming larval activity in response to chlorpyrifos and dichlorvos. In addition, kyphosis and decreased spine length were prominent in Xenopus in response to 10 µM of chlorpyrifos and 0.1 µM dichlorvos. Although diazinon induced no effects on skeletal and cardiac motor activity in either species, it did induce cardiac edemas in zebrafish. Differences in the biological actions of OPs and their differential effects in these 2 vertebrate models demonstrate the importance of using common protocols and multiple models to evaluate the ecotoxicology of OPs. © 2014 SETAC.

  13. Suppressed sympathetic outflow to skeletal muscle, muscle thermogenesis, and activity energy expenditure with calorie restriction.

    Science.gov (United States)

    Almundarij, Tariq I; Gavini, Chaitanya K; Novak, Colleen M

    2017-02-01

    During weight loss, adaptive thermogenesis occurs where energy expenditure (EE) is suppressed beyond that predicted for the smaller body size. Here, we investigated the contributions of resting and nonresting EE to the reduced total EE seen after 3 weeks of 50% calorie restriction (CR) in rats, focusing on activity-associated EE, muscle thermogenesis, and sympathetic outflow. Prolonged food restriction resulted in a 42% reduction in daily EE, through a 40% decrease in resting EE, and a 48% decline in nonresting EE These decreases in EE were significant even when the reductions in body weight and lean mass were taken into account. Along with a decreased caloric need for low-to-moderate-intensity treadmill activity with 50% CR, baseline and activity-related muscle thermogenesis were also suppressed, though the ability to increase muscle thermogenesis above baseline levels was not compromised. When sympathetic drive was measured by assessing norepinephrine turnover (NETO), 50% CR was found to decrease NETO in three of the four muscle groups examined, whereas elevated NETO was found in white adipose tissue of food-restricted rats. Central activation of melanocortin 4 receptors in the ventromedial hypothalamus stimulated this pathway, enhancing activity EE; this was not compromised by 50% CR These data suggest that suppressed activity EE contributes to adaptive thermogenesis during energy restriction. This may stem from decreased sympathetic drive to skeletal muscle, increasing locomotor efficiency and reducing skeletal muscle thermogenesis. The capacity to increase activity EE in response to central stimuli is retained, however, presenting a potential target for preventing weight regain. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

  14. Alterations in core body temperature, locomotor activity, and corticosterone following acute and repeated social defeat of male NMRI mice.

    Science.gov (United States)

    Keeney, A J; Hogg, S; Marsden, C A

    Repeated social defeat of male NMRI mice, coupled with the stress of continuously living opposite a dominant animal, induces a citalopram-reversible increase in anxiety. The experiments reported in the present paper were performed in an attempt to further validate this paradigm by studying the effects of acute and repeated social defeat on corticosterone and the circadian rhythms of core body temperature and locomotor activity, measured by telemetry. Acute social defeat induced a large (controls: 37.14+/-0.29 degrees C; subordinates: 39.79+/-0.33 degrees C) increase in core body temperature and corticosterone (controls: 30.14+/-2.70 ng/ml; subordinates: 89.62+/-9.25 ng/ml). Repeated social defeat (24 defeats) induced a chronic elevation in core body temperature across 24-h (controls: 36.62+/-0.04 degrees C; subordinates: 37.11+/-0.16 degrees C) in subordinate animals and a very large increase in corticosterone (controls: 28.60+/-1.27 ng/ml; subordinates: 441.52+/-8.86 ng/ml). These results illustrate that the chronic social defeat procedure described in this paper induces a state of chronic stress in the subordinate animals. Further studies are warranted to ascertain if the chronic hyperthermia and increases in corticosterone observed in the subordinate animals could be attenuated by chronic antidepressant treatment, thus further extending the predictive validity of this model.

  15. Local tidal regime dictates plasticity of expression of locomotor activity rhythms of American horseshoe crabs,Limulus polyphemus.

    Science.gov (United States)

    Anderson, Rebecca L; Watson, Winsor H; Chabot, Christopher C

    2017-04-01

    While horseshoe crabs Limulus polyphemus from regions with two daily tides express endogenous circatidal (~ 12.4 h) activity rhythms, much less is known about locomotor rhythm expression in horseshoe crabs from other tidal regimes. This study investigated whether horseshoe crabs (1) always express activity rhythms consistent with their natural tides, and (2) can alter activity rhythm expression in response to novel tide cycles. Activity rhythms of animals from environments with two daily tides (Gulf of Maine, 43°6' N/70°52' W, and Massachusetts, 41°32' N/70°40'W), one dominant daily tide (Apalachee Bay, Florida, 29°58' N/84°20' W), and microtides (Indian River Lagoon, Florida, 28°5' N/80°35' W) were recorded in 2011-2013 during three artificial tide conditions: no tides, a 12.4 h tidal cycle, and a 24.8 h tidal cycle. Interestingly, L. polyphemus from the microtidal site ( n = 7) appeared "plastic" in their responses; they were able to express both bimodal and unimodal rhythms in response to different tide cycles. In contrast, the other two populations exhibited more fixed responses: regardless of the tides they were exposed to, animals from areas with one dominant daily tide ( n = 18) consistently expressed unimodal rhythms, while those from areas with two daily tides ( n = 28) generally expressed bimodal rhythms. Rhythms expressed by L. polyphemus thus appear to be a function of endogenous clocks, the tidal cues to which animals are exposed, and tidal cues that animals experience throughout ontogeny.

  16. Locomotor activity influences muscle architecture and bone growth but not muscle attachment site morphology

    Science.gov (United States)

    Rabey, Karyne N.; Green, David J.; Taylor, Andrea B.; Begun, David R.; Richmond, Brian G.; McFarlin, Shannon C.

    2014-01-01

    The ability to make behavioural inferences from skeletal remains is critical to understanding the lifestyles and activities of past human populations and extinct animals. Muscle attachment site (enthesis) morphology has long been assumed to reflect muscle strength and activity during life, but little experimental evidence exists to directly link activity patterns with muscle development and the morphology of their attachments to the skeleton. We used a mouse model to experimentally test how the level and type of activity influences forelimb muscle architecture of spinodeltoideus, acromiodeltoideus, and superficial pectoralis, bone growth rate and gross morphology of their insertion sites. Over an 11-week period, we collected data on activity levels in one control group and two experimental activity groups (running, climbing) of female wild-type mice. Our results show that both activity type and level increased bone growth rates influenced muscle architecture, including differences in potential muscular excursion (fibre length) and potential force production (physiological cross-sectional area). However, despite significant influences on muscle architecture and bone development, activity had no observable effect on enthesis morphology. These results suggest that the gross morphology of entheses is less reliable than internal bone structure for making inferences about an individual’s past behaviour. PMID:25467113

  17. Emotion suppression reduces hippocampal activity during successful memory encoding.

    Science.gov (United States)

    Binder, Julia; de Quervain, Dominique J-F; Friese, Malte; Luechinger, Roger; Boesiger, Peter; Rasch, Björn

    2012-10-15

    People suppressing their emotions while facing an emotional event typically remember it less well. However, the neural mechanisms underlying the impairing effect of emotion suppression on successful memory encoding are not well understood. Because successful memory encoding relies on the hippocampus and the amygdala, we hypothesized that memory impairments due to emotion suppression are associated with down-regulated activity in these brain areas. 59 healthy females were instructed either to simply watch the pictures or to down-regulate their emotions by using a response-focused emotion suppression strategy. Brain activity was recorded using functional magnetic resonance imaging (fMRI), and free recall of pictures was tested afterwards. As expected, suppressing one's emotions resulted in impaired recall of the pictures. On the neural level, the memory impairments were associated with reduced activity in the right hippocampus during successful encoding. No significant effects were observed in the amygdala. In addition, functional connectivity between the hippocampus and the right dorsolateral prefrontal cortex was strongly reduced during emotion suppression, and these reductions predicted free-recall performance. Our results indicate that emotion suppression interferes with memory encoding on the hippocampal level, possibly by decoupling hippocampal and prefrontal encoding processes, suggesting that response-focused emotion suppression might be an adaptive strategy for impairing hippocampal memory formation in highly arousing situations. Copyright © 2012 Elsevier Inc. All rights reserved.

  18. Cocaine-induced locomotor activity is increased by prior handling in adolescent but not adult female rats.

    Science.gov (United States)

    Maldonado, Antoniette M; Kirstein, Cheryl L

    2005-11-15

    Adolescence is a period of transition that is associated with increased levels of stress and a heightened propensity to initiate drug use. Neuronal development is still occurring during this transitional period, which includes the continued development of the dopamine system during the adolescent period. In the present study, the effects of pre-test handling on cocaine-induced locomotor activity were investigated among female adolescent and young adult rats upon presentation to a novel environment. On postnatal days (PND) 41-44 and 56-59 animals were handled (b.i.d.) in the colony room for 3 min. On PND 45 or PND 60, animals were removed from the colony room, weighed, and administered an acute injection of either cocaine or saline and presented to a novel environment where behavior was recorded for 30 min. Adolescent females (PND 45) that were handled prior to cocaine administration demonstrated elevated levels of cocaine-induced activity relative to their age-matched non-handled counterparts and also to their handled-adult counterparts. In contrast, among non-handled animals, young adults (PND 60) exhibited elevated drug-induced locomotion at several time points during the trial. Non-handled adolescent animals demonstrated the previously described "hyporesponsive" behavioral profile relative to their non-handled adult counterparts. The results from the present experiment indicate that adolescent animals may be more sensitive to basic laboratory manipulations such as pre-test handling, and care must be taken when utilizing adolescent animals in behavioral testing. Handling appears to be a sensitive manipulation in elucidating differences in cocaine-induced behavioral activation between ages.

  19. Behaviour and locomotor activity of a migratory catostomid during fishway passage.

    Directory of Open Access Journals (Sweden)

    Ana T Silva

    Full Text Available Fishways have been developed to restore longitudinal connectivity in rivers. Despite their potential for aiding fish passage, fishways may represent a source of significant energetic expenditure for fish as they are highly turbulent environments. Nonetheless, our understanding of the physiological mechanisms underpinning fishway passage of fish is still limited. We examined swimming behaviour and activity of silver redhorse (Moxostoma anisurum during its upriver spawning migration in a vertical slot fishway. We used an accelerometer-derived instantaneous activity metric (overall dynamic body acceleration to estimate location-specific swimming activity. Silver redhorse demonstrated progressive increases in activity during upstream fishway passage. Moreover, location-specific passage duration decreased with an increasing number of passage attempts. Turning basins and the most upstream basin were found to delay fish passage. No relationship was found between basin-specific passage duration and activity and the respective values from previous basins. The results demonstrate that successful fishway passage requires periods of high activity. The resultant energetic expenditure may affect fitness, foraging behaviour and increase susceptibility to predation, compromising population sustainability. This study highlights the need to understand the physiological mechanisms underpinning fishway passage to improve future designs and interpretation of biological evaluations.

  20. ETHANOL-INDUCED LOCOMOTOR ACTIVITY IN ADOLESCENT RATS AND THE RELATIONSHIP WITH ETHANOL-INDUCED CONDITIONED PLACE PREFERENCE AND CONDITIONED TASTE AVERSION

    OpenAIRE

    Acevedo, María Belén; Nizhnikov, Michael E.; Spear, Norman E.; Molina, Juan C.; Pautassi, Ricardo Marcos

    2012-01-01

    Adolescent rats exhibit ethanol-induced locomotor activity (LMA), which is considered an index of ethanol’s motivational properties likely to predict ethanol self-administration, but few studies have reported or correlated ethanol-induced LMA with conditioned place preference by ethanol at this age. The present study assessed age-related differences in ethanol’s motor stimulating effects and analysed the association between ethanol-induced LMA and conventional measures of ethanol-induced rein...

  1. The effects of tricyclic and 'atypical' antidepressants on spontaneous locomotor activity in rodents.

    Science.gov (United States)

    Tucker, J C; File, S E

    1986-01-01

    With the exception of amineptin, buproprion and nomifensine all tricyclic and 'atypical' antidepressants have been reported to reduce spontaneous motor activity in rodents, after both acute and chronic administration. However, with the diversity of chemical actions of these drugs it is unlikely that a single neurochemical mechanism is underlying this one behavioral effect. These widespread sedative effects have implications for interpreting behavioral changes in other test situations, since sedation generally occurs at doses that fall within the dose-range effective in other tests. We also review the effects on spontaneous motor activity of withdrawal from chronic antidepressant treatment.

  2. Risperidone-induced weight gain and reduced locomotor activity in juvenile female rats: The role of histaminergic and NPY pathways.

    Science.gov (United States)

    Lian, Jiamei; De Santis, Michael; He, Meng; Deng, Chao

    2015-01-01

    Second generation antipsychotic drugs (SGAs) such as risperidone are increasingly prescribed (mostly for off-label use) to children and adolescents for treating various mental disorders. SGAs cause serious weight gain/obesity and other metabolic side-effects. This study aimed to establish an animal model of risperidone-induced weight gain in female juvenile rats, and to investigate the effects of risperidone on the expression of hypothalamic histaminergic H1 receptors (H1R) and neuropeptides, and their association with weight gain. Female Sprague Dawley rats were treated orally with risperidone (0.3mg/kg, 3 times/day) or vehicle (control) starting from postnatal day (PD) 23 (±1 day) for 3 weeks (a period corresponding to the childhood-adolescent period in humans). In the female juvenile rats, risperidone treatment increased food intake and body weight gain, which started to appear after 12 days' treatment. Risperidone also significantly decreased the locomotor activity of the female rats. Consistently, risperidone significantly elevated mRNA expression of hypothalamic H1R, neuropeptide Y (NPY), and agouti-related peptide (AgRP) compared to controls, and H1R and NPY levels were correlated with risperidone enhanced weight gain and food intake in the female juvenile rats. However, risperidone did not affect hypothalamic proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) mRNA expression. Therefore, these results suggested that risperidone elevated appetite and body weight gain in juveniles via regulation of the hypothalamic H1R, NPY and AgRP pathways, as well as by reducing activity. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Hyperleptinemia During Pregnancy Decreases Adult Weight of Offspring and Is Associated With Increased Offspring Locomotor Activity in Mice.

    Science.gov (United States)

    Pollock, Kelly E; Stevens, Damaiyah; Pennington, Kathleen A; Thaisrivongs, Rose; Kaiser, Jennifer; Ellersieck, Mark R; Miller, Dennis K; Schulz, Laura Clamon

    2015-10-01

    Pregnant women who are obese or have gestational diabetes mellitus have elevated leptin levels and their children have an increased risk for child and adult obesity. The goals of this study were to determine whether offspring weights are altered by maternal hyperleptinemia, and whether this occurs via behavioral changes that influence energy balance. We used 2 hyperleptinemic mouse models. The first was females heterozygous for a leptin receptor mutation (DB/+), which were severely hyperleptinemic, and that were compared with wild-type females. The second model was wild-type females infused with leptin (LEP), which were moderately hyperleptinemic, and were compared with wild-type females infused with saline (SAL). Total food consumption, food preference, locomotor activity, coordinated motor skills, and anxiety-like behaviors were assessed in wild-type offspring from each maternal group at 3 postnatal ages: 4-6, 11-13, and 19-21 weeks. Half the offspring from each group were then placed on a high-fat diet, and behaviors were reassessed. Adult offspring from both groups of hyperleptinemic dams weighed less than their respective controls beginning at 23 weeks of age, independent of diet or sex. Weight differences were not explained by food consumption or preference, because female offspring from hyperleptinemic dams tended to consume more food and had reduced preference for palatable, high-fat and sugar, food compared with controls. Offspring from DB/+ dams were more active than offspring of controls, as were female offspring of LEP dams. Maternal hyperleptinemia during pregnancy did not predispose offspring to obesity, and in fact, reduced weight gain.

  4. Cold suppresses agonist-induced activation of TRPV1.

    Science.gov (United States)

    Chung, M-K; Wang, S

    2011-09-01

    Cold therapy is frequently used to reduce pain and edema following acute injury or surgery such as tooth extraction. However, the neurobiological mechanisms of cold therapy are not completely understood. Transient receptor potential vanilloid 1 (TRPV1) is a capsaicin- and heat-gated nociceptive ion channel implicated in thermosensation and pathological pain under conditions of inflammation or injury. Although capsaicin-induced nociception, neuropeptide release, and ionic currents are suppressed by cold, it is not known if cold suppresses agonist-induced activation of recombinant TRPV1. We demonstrate that cold strongly suppressed the activation of recombinant TRPV1 by multiple agonists and capsaicin-evoked currents in trigeminal ganglia neurons under normal and phosphorylated conditions. Cold-induced suppression was partially impaired in a TRPV1 mutant that lacked heat-mediated activation and potentiation. These results suggest that cold-induced suppression of TRPV1 may share a common molecular basis with heat-induced potentiation, and that allosteric inhibition may contribute, in part, to the cold-induced suppression. We also show that combination of cold and a specific antagonist of TRPV1 can produce an additive suppression. Our results provide a mechanistic basis for cold therapy and may enhance anti-nociceptive approaches that target TRPV1 for managing pain under inflammation and tissue injury, including that from tooth extraction.

  5. Sheltering behavior and locomotor activity in 11 genetically diverse common inbred mouse strains using home-cage monitoring.

    Directory of Open Access Journals (Sweden)

    Maarten Loos

    Full Text Available Functional genetic analyses in mice rely on efficient and in-depth characterization of the behavioral spectrum. Automated home-cage observation can provide a systematic and efficient screening method to detect unexplored, novel behavioral phenotypes. Here, we analyzed high-throughput automated home-cage data using existing and novel concepts, to detect a plethora of genetic differences in spontaneous behavior in a panel of commonly used inbred strains (129S1/SvImJ, A/J, C3H/HeJ, C57BL/6J, BALB/cJ, DBA/2J, NOD/LtJ, FVB/NJ, WSB/EiJ, PWK/PhJ and CAST/EiJ. Continuous video-tracking observations of sheltering behavior and locomotor activity were segmented into distinguishable behavioral elements, and studied at different time scales, yielding a set of 115 behavioral parameters of which 105 showed highly significant strain differences. This set of 115 parameters was highly dimensional; principal component analysis identified 26 orthogonal components with eigenvalues above one. Especially novel parameters of sheltering behavior and parameters describing aspects of motion of the mouse in the home-cage showed high genetic effect sizes. Multi-day habituation curves and patterns of behavior surrounding dark/light phase transitions showed striking strain differences, albeit with lower genetic effect sizes. This spontaneous home-cage behavior study demonstrates high dimensionality, with a strong genetic contribution to specific sets of behavioral measures. Importantly, spontaneous home-cage behavior analysis detects genetic effects that cannot be studied in conventional behavioral tests, showing that the inclusion of a few days of undisturbed, labor extensive home-cage assessment may greatly aid gene function analyses and drug target discovery.

  6. Treatment with pentylenetetrazole (PTZ) and 4-aminopyridine (4-AP) differently affects survival, locomotor activity, and biochemical markers in Drosophila melanogaster.

    Science.gov (United States)

    Soares, Deividi C S; Portela, José L R; Roos, Daniel H; Rodrigues, Nathane R; Gomes, Karen K; Macedo, Giulianna E; Posser, Thais; Franco, Jeferson L; Hassan, Waseem; Puntel, Robson L

    2017-10-10

    PTZ is a convulsive agent that acts via selective blockage of GABA A receptor channels, whereas 4-AP leads to a convulsive episode via blockage of K + channels. However, the mechanism(s) by which pentylenetetrazole (PTZ) and 4-aminopyridine (4-AP) cause toxicity to Drosophila melanogaster needs to be properly explored, once it will help in establishing an alternative model for development of proper therapeutic strategies and also to counteract the changes associated with exposure to both epileptic drugs. For the purpose, we investigated the effects of exposure (48 h) to PTZ (60 mM) and/or 4-AP (20 mM) on survival, locomotor performance, and biochemical markers in the body and/or head of flies. 4-AP-fed flies presented a higher incidence of mortality and a worse performance in the open field test as compared to non-treated flies. 4-AP also caused a significant increase in the reactive species (RS) and protein carbonyl (PC) content in the body and head. Also a significant increase in catalase and acetylcholinesterase (AChE) activities was observed in the body. In the same vein, PTZ exposure resulted in a significant increase in RS, thiobarbituric acid reactive substances (TBARS), PC content, and catalase activity in the body. PTZ exposure also caused a significant increase in AChE activity both in body and head. It is important to note that PTZ-treated flies also down-regulated the NRF 2 expression. Moreover, both 4AP- and PTZ-fed flies presented a significant decrease in MTT reduction, down-regulation, and inhibition of SOD in body. However, SOD was significantly more active in the head of both 4-AP and PTZ-treated flies. Our findings provide evidence regarding the toxicological potential of both PTZ and/or 4-AP to flies. This model will help in decoding the underlying toxicological mechanisms of the stated drugs. It will also help to properly investigate the therapeutic strategies and to counteract the drastic changes associated with both epileptogenic drugs.

  7. Synchronization to light and mealtime of daily rhythms of locomotor activity, plasma glucose and digestive enzymes in the Nile tilapia (Oreochromis niloticus).

    Science.gov (United States)

    Guerra-Santos, Bartira; López-Olmeda, José Fernando; de Mattos, Bruno Olivetti; Baião, Alice Borba; Pereira, Denise Soledade Peixoto; Sánchez-Vázquez, Francisco Javier; Cerqueira, Robson Bahia; Albinati, Ricardo Castelo Branco; Fortes-Silva, Rodrigo

    2017-02-01

    The light-dark cycle and feeding can be the most important factors acting as synchronizers of biological rhythms. In this research we aimed to evaluate synchronization to feeding schedule of daily rhythms of locomotor activity and digestive enzymes of tilapia. For that purpose, 120 tilapias (65.0±0.6g) were distributed in 12 tanks (10 fish per tank) and divided into two groups. One group was fed once a day at 11:00h (zeitgeber time, ZT6) (ML group) and the other group was fed at 23:00h (ZT18) (MD group). The fish were anesthetized to collect samples of blood, stomach and midgut at 4-hour intervals over a period of 24h. Fish fed at ML showed a diurnal locomotor activity (74% of the total daily activity occurring during the light phase) and synchronization to the feeding schedule, as this group showed anticipation to the feeding time. Fish fed at MD showed a disruption in the pattern of locomotor activity and became less diurnal (59%). Alkaline protease activity in the midgut showed daily rhythm with the achrophase at the beginning of the dark phase in both ML and MD groups. Acid protease and amylase did not show significant daily rhythms. Plasma glucose showed a daily rhythm with the achrophase shifted by 12h in the ML and MD groups. These results revealed that the feeding time and light cycle synchronize differently the daily rhythms of behavior, digestive physiology and plasma metabolites in the Nile tilapia, which indicate the plasticity of the circadian system and its synchronizers. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Repeated MDMA administration increases MDMA-produced locomotor activity and facilitates the acquisition of MDMA self-administration: role of dopamine D2 receptor mechanisms.

    Science.gov (United States)

    van de Wetering, Ross; Schenk, Susan

    2017-04-01

    Repeated exposure to ±3, 4-methylenedioxymethamphetamine (MDMA) produces sensitization to MDMA-produced hyperactivity, but the mechanisms underlying the development of this sensitized response or the relationship to the reinforcing effects of MDMA is unknown. This study determined the effect of a sensitizing regimen of MDMA exposure on the acquisition of MDMA self-administration and investigated the role of dopamine D 2 receptor mechanisms. Rats received the selective D 2 antagonist, eticlopride (0.0 or 0.3 mg/kg, i.p.) and MDMA (0.0 or 10.0 mg/kg, i.p.) during a five-day pretreatment regimen. Two days following the final session, the locomotor activating effects of MDMA (5 mg/kg, i.p.) and the latency to acquisition of MDMA self-administration were determined. Pretreatment with MDMA enhanced the locomotor activating effects of MDMA and facilitated the acquisition of MDMA self-administration. Administration of eticlopride during MDMA pretreatment completely blocked the development of sensitization to MDMA-produced hyperactivity but failed to significantly alter the facilitated acquisition of MDMA self-administration. Pretreatment with eticlopride alone facilitated the acquisition of self-administration. These data suggest that repeated MDMA exposure sensitized both the locomotor activating and reinforcing effects of MDMA. Activation of D 2 receptors during MDMA pretreatment appears critical for the development of sensitization to MDMA-produced hyperactivity. The role of D 2 receptor mechanisms in the development of sensitization to the reinforcing effects of MDMA is equivocal.

  9. Next Generation Active Buffet Suppression System

    Science.gov (United States)

    Galea, Stephen C.; Ryall, Thomas G.; Henderson, Douglas A.; Moses, Robert W.; White, Edward V.; Zimcik, David G.

    2003-01-01

    Buffeting is an aeroelastic phenomenon that is common to high performance aircraft, especially those with twin vertical tails like the F/A-18, at high angles of attack. These loads result in significant random stresses, which may cause fatigue damage leading to restricted capabilities and availability of the aircraft. This paper describes an international collaborative research activity among Australia, Canada and the United States involving the use of active structural control to alleviate the damaging structural response to these loads. The research program is being co-ordinated by the Air Force Research Laboratory (AFRL) and is being conducted under the auspices of The Technical Cooperative Program (TTCP). This truly unique collaborative program has been developed to enable each participating country to contribute resources toward a program that coalesces a broad range of technical knowledge and expertise into a single investigation. This collaborative program is directed toward a full-scale test of an F/A-18 empennage, which is an extension of an earlier initial test. The current program aims at applying advanced directional piezoactuators, the aircraft rudder, switch mode amplifiers and advanced control strategies on a full-scale structure to demonstrate the enhanced performance and capability of the advanced active BLA control system in preparation for a flight test demonstration.

  10. Effects of chronic prenatal MK-801 treatment on object recognition, cognitive flexibility, and drug-induced locomotor activity in juvenile and adult rat offspring.

    Science.gov (United States)

    Gallant, S; Welch, L; Martone, P; Shalev, U

    2017-06-15

    Patients with schizophrenia display impaired cognitive functioning and increased sensitivity to psychomimetic drugs. The neurodevelopmental hypothesis of schizophrenia posits that disruption of the developing brain predisposes neural networks to lasting structural and functional abnormalities resulting in the emergence of such symptoms in adulthood. Given the critical role of the glutamatergic system in early brain development, we investigated whether chronic prenatal exposure to the glutamate NMDA receptor antagonist, MK-801, induces schizophrenia-like behavioural and neurochemical changes in juvenile and adult rats. Pregnant Long-Evans rats were administered saline or MK-801 (0.1mg/kg; s.c.) at gestation day 7-19. Object recognition memory and cognitive flexibility were assessed in the male offspring using a novel object preference task and a maze-based set-shifting procedure, respectively. Locomotor-activating effects of acute amphetamine and MK-801 were also assessed. Adult, but not juvenile, prenatally MK-801-treated rats failed to show novel object preference after a 90min delay, suggesting that object recognition memory may have been impaired. In addition, the set-shifting task revealed impaired acquisition of a new rule in adult prenatally MK-801-treated rats compared to controls. This deficit appeared to be driven by regression to the previously learned behaviour. There were no significant differences in drug-induced locomotor activity in juvenile offspring or in adult offspring following acute amphetamine challenges. Unexpectedly, MK-801-induced locomotor activity in adult prenatally MK-801-treated rats was lower compared to controls. Glutamate transmission dysfunction during early development may modify behavioural parameters in adulthood, though these parameters do not appear to model deficits observed in schizophrenia. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Nanomolar oxytocin synergizes with weak electrical afferent stimulation to activate the locomotor CpG of the rat spinal cord in vitro.

    Directory of Open Access Journals (Sweden)

    Francesco Dose

    Full Text Available Synergizing the effect of afferent fibre stimulation with pharmacological interventions is a desirable goal to trigger spinal locomotor activity, especially after injury. Thus, to better understand the mechanisms to optimize this process, we studied the role of the neuropeptide oxytocin (previously shown to stimulate locomotor networks on network and motoneuron properties using the isolated neonatal rat spinal cord. On motoneurons oxytocin (1 nM-1 μM generated sporadic bursts with superimposed firing and dose-dependent depolarization. No desensitization was observed despite repeated applications. Tetrodotoxin completely blocked the effects of oxytocin, demonstrating the network origin of the responses. Recording motoneuron pool activity from lumbar ventral roots showed oxytocin mediated depolarization with synchronous bursts, and depression of reflex responses in a stimulus and peptide-concentration dependent fashion. Disinhibited bursting caused by strychnine and bicuculline was accelerated by oxytocin whose action was blocked by the oxytocin antagonist atosiban. Fictive locomotion appeared when subthreshold concentrations of NMDA plus 5HT were coapplied with oxytocin, an effect prevented after 24 h incubation with the inhibitor of 5HT synthesis, PCPA. When fictive locomotion was fully manifested, oxytocin did not change periodicity, although cycle amplitude became smaller. A novel protocol of electrical stimulation based on noisy waveforms and applied to one dorsal root evoked stereotypic fictive locomotion. Whenever the stimulus intensity was subthreshold, low doses of oxytocin triggered fictive locomotion although oxytocin per se did not affect primary afferent depolarization evoked by dorsal root pulses. Among the several functional targets for the action of oxytocin at lumbar spinal cord level, the present results highlight how small concentrations of this peptide could bring spinal networks to threshold for fictive locomotion in

  12. Chronic low-level arsenic exposure causes gender-specific alterations in locomotor activity, dopaminergic systems, and thioredoxin expression in mice

    International Nuclear Information System (INIS)

    Bardullas, U.; Limon-Pacheco, J.H.; Giordano, M.; Carrizales, L.; Mendoza-Trejo, M.S.; Rodriguez, V.M.

    2009-01-01

    Arsenic (As) is a toxic metalloid widely present in the environment. Human exposure to As has been associated with the development of skin and internal organ cancers and cardiovascular disorders, among other diseases. A few studies report decreases in intelligence quotient (IQ), and sensory and motor alterations after chronic As exposure in humans. On the other hand, studies of rodents exposed to high doses of As have found alterations in locomotor activity, brain neurochemistry, behavioral tasks, and oxidative stress. In the present study both male and female C57Bl/6J mice were exposed to environmentally relevant doses of As such as 0.05, 0.5, 5.0, or 50 mg As/L of drinking water for 4 months, and locomotor activity was assessed every month. Male mice presented hyperactivity in the group exposed to 0.5 mg As/L and hypoactivity in the group exposed to 50 mg As/L after 4 months of As exposure, whereas female mice exposed to 0.05, 0.5, and 5.0 mg As/L exhibited hyperactivity in every monthly test during As exposure. Furthermore, striatal and hypothalamic dopamine content was decreased only in female mice. Also decreases in tyrosine hydroxylase (TH) and cytosolic thioredoxin (Trx-1) mRNA expression in striatum and nucleus accumbens were observed in male and female mice, respectively. These results indicate that chronic As exposure leads to gender-dependent alterations in dopaminergic markers and spontaneous locomotor activity, and down-regulation of the antioxidant capacity of the brain.

  13. P2X7 receptors in body temperature, locomotor activity, and brain mRNA and lncRNA responses to sleep deprivation.

    Science.gov (United States)

    Davis, Christopher J; Taishi, Ping; Honn, Kimberly A; Koberstein, John N; Krueger, James M

    2016-12-01

    The ionotropic purine type 2X7 receptor (P2X7R) is a nonspecific cation channel implicated in sleep regulation and brain cytokine release. Many endogenous rhythms covary with sleep, including locomotor activity and core body temperature. Furthermore, brain-hypothalamic cytokines and purines play a role in the regulation of these physiological parameters as well as sleep. We hypothesized that these parameters are also affected by the absence of the P2X7 receptor. Herein, we determine spontaneous expression of body temperature and locomotor activity in wild-type (WT) and P2X7R knockout (KO) mice and how they are affected by sleep deprivation (SD). We also compare hypothalamic, hippocampal, and cortical cytokine- and purine-related receptor and enzyme mRNA expressions before and after SD in WT and P2X7RKO mice. Next, in a hypothesis-generating survey of hypothalamic long noncoding (lnc) RNAs, we compare lncRNA expression levels between strains and after SD. During baseline conditions, P2X7RKO mice had attenuated temperature rhythms compared with WT mice, although locomotor activity patterns were similar in both strains. After 6 h of SD, body temperature and locomotion were enhanced to a greater extent in P2X7RKO mice than in WT mice during the initial 2-3 h after SD. Baseline mRNA levels of cortical TNF-α and P2X4R were higher in the KO mice than WT mice. In response to SD, the KO mice failed to increase hypothalamic adenosine deaminase and P2X4R mRNAs. Further, hypothalamic lncRNA expressions varied by strain, and with SD. Current data are consistent with a role for the P2X7R in thermoregulation and lncRNA involvement in purinergic signaling. Copyright © 2016 the American Physiological Society.

  14. CuZn-superoxide dismutase transgenic mice: no effect on longevity, locomotor activity and 3H-mazindol and 3H-spiperone binding over 19 months.

    Science.gov (United States)

    Gallagher, I M; Jenner, P; Glover, V; Clow, A

    2000-08-11

    This study was designed to determine whether CuZn-superoxide dismutase (SOD) is neuroprotective against aging in the nigrostriatal tract. Twenty-four male mice transgenic for human CuZnSOD, resulting in overexpression of the cytosolic enzyme, were compared with 11 matched controls over 19 months. There was no difference in longevity, locomotor activity, or 3H-mazindol or 3H-spiperone binding in the nigrostriatal tract in the two groups. Thus there was no evidence that increased CuZnSOD was neuroprotective in this model.

  15. Fenproporex increases locomotor activity and alters energy metabolism, and mood stabilizers reverse these changes: a proposal for a new animal model of mania.

    Science.gov (United States)

    Rezin, Gislaine T; Furlanetto, Camila B; Scaini, Giselli; Valvassori, Samira S; Gonçalves, Cinara L; Ferreira, Gabriela K; Jeremias, Isabela C; Resende, Wilson R; Cardoso, Mariane R; Varela, Roger B; Quevedo, João; Streck, Emilio L

    2014-04-01

    Fenproporex (Fen) is converted in vivo into amphetamine, which is used to induce mania-like behaviors in animals. In the present study, we intend to present a new animal model of mania. In order to prove through face, construct, and predictive validities, we evaluated behavioral parameters (locomotor activity, stereotypy activity, and fecal boli amount) and brain energy metabolism (enzymes citrate synthase; malate dehydrogenase; succinate dehydrogenase; complexes I, II, II-III, and IV of the mitochondrial respiratory chain; and creatine kinase) in rats submitted to acute and chronic administration of fenproporex, treated with lithium (Li) and valproate (VPA). The administration of Fen increased locomotor activity and decreased the activity of Krebs cycle enzymes, mitochondrial respiratory chain complexes, and creatine kinase, in most brain structures evaluated. In addition, treatment with mood stabilizers prevented and reversed this effect. Our results are consistent with the literature that demonstrates behavioral changes and mitochondrial dysfunction caused by psychostimulants. These findings suggest that chronic administration of Fen may be a potential animal model of mania.

  16. Effects of voluntary wheel running on heart rate, body temperature, and locomotor activity in response to acute and repeated stressor exposures in rats.

    Science.gov (United States)

    Masini, Cher V; Nyhuis, Tara J; Sasse, Sarah K; Day, Heidi E W; Campeau, Serge

    2011-05-01

    Stress often negatively impacts physical and mental health but it has been suggested that voluntary physical activity may benefit health by reducing some of the effects of stress. The present experiments tested whether voluntary exercise can reduce heart rate, core body temperature and locomotor activity responses to acute (novelty or loud noise) or repeated stress (loud noise). After 6 weeks of running-wheel access, rats exposed to a novel environment had reduced heart rate, core body temperature, and locomotor activity responses compared to rats housed under sedentary conditions. In contrast, none of these measures were different between exercised and sedentary rats following acute 30-min noise exposures, at either 85 or 98 dB. Following 10 weeks of running-wheel access, both groups displayed significant habituation of all these responses to 10 consecutive daily 30-min presentations of 98 dB noise stress. However, the extent of habituation of all three responses was significantly enhanced in exercised compared to sedentary animals on the last exposure to noise. These results suggest that in physically active animals, under some conditions, acute responses to stress exposure may be reduced, and response habituation to repeated stress may be enhanced, which ultimately may reduce the negative and cumulative impact of stress.

  17. Repeated administration of phytocannabinoid Δ(9)-THC or synthetic cannabinoids JWH-018 and JWH-073 induces tolerance to hypothermia but not locomotor suppression in mice, and reduces CB1 receptor expression and function in a brain region-specific manner.

    Science.gov (United States)

    Tai, S; Hyatt, W S; Gu, C; Franks, L N; Vasiljevik, T; Brents, L K; Prather, P L; Fantegrossi, W E

    2015-12-01

    These studies probed the relationship between intrinsic efficacy and tolerance/cross-tolerance between ∆(9)-THC and synthetic cannabinoid drugs of abuse (SCBs) by examining in vivo effects and cellular changes concomitant with their repeated administration in mice. Dose-effect relationships for hypothermic effects were determined in order to confirm that SCBs JWH-018 and JWH-073 are higher efficacy agonists than ∆(9)-THC in mice. Separate groups of mice were treated with saline, sub-maximal hypothermic doses of JWH-018 or JWH-073 (3.0mg/kg or 10.0mg/kg, respectively) or a maximally hypothermic dose of 30.0mg/kg ∆(9)-THC once per day for 5 consecutive days while core temperature and locomotor activity were monitored via biotelemetry. Repeated administration of all drugs resulted in tolerance to hypothermic effects, but not locomotor effects, and this tolerance was still evident 14 days after the last drug administration. Further studies treated mice with 30.0mg/kg ∆(9)-THC once per day for 4 days, then tested with SCBs on day 5. Mice with a ∆(9)-THC history were cross-tolerant to both SCBs, and this cross-tolerance also persisted 14 days after testing. Select brain regions from chronically treated mice were examined for changes in CB1 receptor expression and function. Expression and function of hypothalamic CB1Rs were reduced in mice receiving chronic drugs, but cortical CB1R expression and function were not altered. Collectively, these data demonstrate that repeated ∆(9)-THC, JWH-018 and JWH-073 can induce long-lasting tolerance to some in vivo effects, which is likely mediated by region-specific downregulation and desensitization of CB1Rs. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. Blood pressures, heart rate and locomotor activity during salt loading and angiotensin II infusion in protease-activated receptor 2 (PAR2 knockout mice

    Directory of Open Access Journals (Sweden)

    Halfyard Sarah J

    2008-10-01

    Full Text Available Abstract Background In this study we used radiotelemetry to measure hemodynamic variables and locomotor activity in conscious unrestrained male Protease-Activated Receptor 2 (PAR-2 knockout mice in order to provide a detailed assessment of their blood pressure phenotype. In addition we tested for an influence of PAR-2 on salt-sensitivity (8% versus 0.5% NaCl diet, 2.5 weeks and angiotensin II-induced hypertension (1 μg Ile5-angiotensin II/kg/min versus 0.25 μl/h saline, 2 weeks. Results Systolic arterial pressures of PAR-2 -/- (129 ± 1 mmHg, n = 21, P P Conclusion The data indicated gene knockout of PAR-2 was associated with a modest change in blood pressure phenotype. PAR-2 -/- mice exhibited moderate elevation of systolic arterial and pulse pressures, yet no increased diastolic arterial pressure, no increased blood pressure responses to high salt diet and a subtle difference in the time course of the blood pressure responses to angiotensin II infusion.

  19. Dopamine and the Brainstem Locomotor Networks: From Lamprey to Human

    Directory of Open Access Journals (Sweden)

    Dimitri Ryczko

    2017-05-01

    Full Text Available In vertebrates, dopamine neurons are classically known to modulate locomotion via their ascending projections to the basal ganglia that project to brainstem locomotor networks. An increased dopaminergic tone is associated with increase in locomotor activity. In pathological conditions where dopamine cells are lost, such as in Parkinson's disease, locomotor deficits are traditionally associated with the reduced ascending dopaminergic input to the basal ganglia. However, a descending dopaminergic pathway originating from the substantia nigra pars compacta was recently discovered. It innervates the mesencephalic locomotor region (MLR from basal vertebrates to mammals. This pathway was shown to increase locomotor output in lampreys, and could very well play an important role in mammals. Here, we provide a detailed account on the newly found dopaminergic pathway in lamprey, salamander, rat, monkey, and human. In lampreys and salamanders, dopamine release in the MLR is associated with the activation of reticulospinal neurons that carry the locomotor command to the spinal cord. Dopamine release in the MLR potentiates locomotor movements through a D1-receptor mechanism in lampreys. In rats, stimulation of the substantia nigra pars compacta elicited dopamine release in the pedunculopontine nucleus, a known part of the MLR. In a monkey model of Parkinson's disease, a reduced dopaminergic innervation of the brainstem locomotor networks was reported. Dopaminergic fibers are also present in human pedunculopontine nucleus. We discuss the conserved locomotor role of this pathway from lamprey to mammals, and the hypothesis that this pathway could play a role in the locomotor deficits reported in Parkinson's disease.

  20. Active Suppression of Rotating Stall Inception with Distributed Jet Actuation

    Directory of Open Access Journals (Sweden)

    Huu Duc Vo

    2007-01-01

    Full Text Available An analytical and experimental investigation of the effectiveness of full-span distributed jet actuation for active suppression of long length-scale rotating stall inception is carried out. Detailed modeling and experimental verification highlight the important effects of mass addition, discrete injectors, and feedback dynamics, which may be overlooked in preliminary theoretical studies of active control with jet injection. A model of the compression system incorporating nonideal injection and feedback dynamics is verified with forced response measurements to predict the right trends in the movement of the critical pole associated with the stall precursor. Active control experiments with proportional feedback control show that the predicted stall precursors are suppressed to give a 5.5% range extension in compressor flow coefficient. In addition, results suggest that the proposed model could be used to design a more sophisticated controller to further improve performance while reducing actuator bandwidth requirements.

  1. Effect of Intraperitoneal Administration of Hydroalcoholic and Hexanic Extract of Heated Female Cannabis Sativa Flowertops on Anxiety Behavior, Motor Coordination and Locomotor Activity in the Male Rats

    Directory of Open Access Journals (Sweden)

    B Farhadi Moghadam

    2016-01-01

    Full Text Available Introduction: Decarboxylated phytocannabinoids activates CB1 receptors of endocannabinoid system in the central nervous system. Endocannabinoid system interacts with dopaminergic and serotoninergic systems, which seems to be effective on the behavior processes. Therefore, this study aimed to investigate the effect of hydroalcoholic and hexanic extract of heated female Cannabis sativa flowertops containing decarboxylated cannabinoids on anxiety, motor coordination and locomotor activity. Methods: In this experimental study, adult male Wistar rats were randomly (200 to 250 g used in two groups(n=7 of control and sham (administration of the solution vehicle (Tween 80, ethanol and saline with 1:1:8 proportions. IP administration of hydroalcoholic extract (50mg/kg dosage, and hexanic extract (50mg/kg dosage were applied. The elevated plus maze, open field and rotarod apparatus were used in order to measure the anxiety, locomotor activity and motor coordination in each group, respectively. Moreover, the data analysis was carried out by one-way ANOVA and Neumann-keuls post-hoc test. Results: The study results indicated that IP administration of hexanic extract (50mg/kg dosage significantly reduced the numbers of entries into the open arms (P<0.05 as well as time of stay in the open arms (P<0.01 in evaluated plus maze. Furthermore, motor activity (P <0.01 and time coordination (P <0.001 were reported to significantly reduce. Conclusion: The study findings revealed thst administration of hexanic extract has probably more decarboxylated cannabinoids than hydroalcoholic extract resulting in a decrease in the motor activity and time of motor coordination, yet an increase in anxiety via activation of CB1 receptors.

  2. Adaptive Active Noise Suppression Using Multiple Model Switching Strategy

    Directory of Open Access Journals (Sweden)

    Quanzhen Huang

    2017-01-01

    Full Text Available Active noise suppression for applications where the system response varies with time is a difficult problem. The computation burden for the existing control algorithms with online identification is heavy and easy to cause control system instability. A new active noise control algorithm is proposed in this paper by employing multiple model switching strategy for secondary path varying. The computation is significantly reduced. Firstly, a noise control system modeling method is proposed for duct-like applications. Then a multiple model adaptive control algorithm is proposed with a new multiple model switching strategy based on filter-u least mean square (FULMS algorithm. Finally, the proposed algorithm was implemented on Texas Instruments digital signal processor (DSP TMS320F28335 and real time experiments were done to test the proposed algorithm and FULMS algorithm with online identification. Experimental verification tests show that the proposed algorithm is effective with good noise suppression performance.

  3. Differential effects of antipsychotic and propsychotic drugs on prepulse inhibition and locomotor activity in Roman high- (RHA) and low-avoidance (RLA) rats

    DEFF Research Database (Denmark)

    Oliveras, Ignasi; Sánchez-González, Ana; Sampedro-Viana, Daniel

    2017-01-01

    in either strain, but decreased locomotion in a dose-dependent manner in both rat strains. The mixed dopamine D1/D2 agonist, apomorphine, at the dose of 0.05 mg/kg, decreased PPI in RHA-I, but not RLA-I rats. The hallucinogen drug DOI (5-HT2A agonist; 0.1-1.0 mg/kg) disrupted PPI in RLA-I rats in a dose-dependent...... acutely administered propsychotic (DOI, MK-801) and antipsychotic drugs (haloperidol, clozapine), as well as apomorphine, on prepulse inhibition (PPI) of startle and locomotor activity (activity cages). RESULTS: RHA-I rats display a consistent deficit of PPI compared with RLA-I rats. The typical...

  4. Effects of short-term fasting on stress physiology, body condition, and locomotor activity in wintering male white-crowned sparrows.

    Science.gov (United States)

    Krause, Jesse S; Pérez, Jonathan H; Meddle, Simone L; Wingfield, John C

    2017-08-01

    For wild free-living animals the availability of food resources can be greatly affected by environmental perturbations such as weather events. In response to environmental perturbations, animals activate the hypothalamic-pituitary-adrenal (HPA) axis to adjust physiology and behavior. The literature asserts that during weather events food intake declines leading to changes in HPA axis activity, as measured by both baseline and stress-induced glucocorticoid concentrations. Here we investigated how body condition, locomotor activity, and stress physiology were affected by varying lengths of a fast (1, 2, 6, and 24h; similar to that experienced by free-living birds) compared to when food was provided ad libitum in captive wintering male white-crowned sparrows, Zonotrichia leucophrys gambelii, exposed to a short day photoperiod. Baseline corticosterone concentrations were increased for all fasting durations but were highest in 6 and 24h fasted birds. Stress-induced corticosterone was elevated in 1h fasted birds with a trend for the 2h of fast; no other differences were found. Baseline corticosterone concentrations were negatively related to both total fat scores and body mass. All birds lost body mass regardless of fast length but birds fasted for 24h lost the most. Fat scores declined in the 6 and 24h groups, and no measureable changes were detected in pectoralis muscle profile. Locomotor activity was increased over the entire period in which food was removed regardless of fasting duration. Together this suggests that reduced food availability is responsible, at least in part, for the rapid elevation both baseline corticosterone under any duration of fast and stress-induced concentrations during short-term fasts. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  5. Global suppression of electrocortical activity in unilateral perinatal thalamic stroke.

    LENUS (Irish Health Repository)

    Kharoshankaya, Liudmila

    2014-07-01

    We present an unusual case of persistent generalized electroencephalography (EEG) suppression and right-sided clonic seizures in a male infant born at 40(+2) weeks\\' gestation, birthweight 3240g, with an isolated unilateral thalamic stroke. The EEG at 13 hours after birth showed a generalized very low amplitude background pattern, which progressed to frequent electrographic seizures over the left hemisphere. The interictal background EEG pattern remained grossly abnormal over the next 48 hours, showing very low background amplitudes (<10μV). Magnetic resonance imaging revealed an isolated acute left-sided thalamic infarction. This is the first description of severe global EEG suppression caused by an isolated unilateral thalamic stroke and supports the role of the thalamus as the control centre for cortical electrical activity.

  6. Locomotor activity of Cycloneda sanguinea (Coleoptera: Coccinellidae exposed to volatile semiochemicals and to direct contact with the odour source

    Directory of Open Access Journals (Sweden)

    Guillermo E. HEIT

    2007-01-01

    Full Text Available Cycloneda sanguinea (Linnaeus (Coleoptera: Coccinellidae es un predador polífago oportunista y cuando su menú está dominado por áfidos, es esperable un comportamiento complejo de forrajeo. Un movimiento activo, caracterizado por alta actividad locomotriz, juega un rol importante en la búsqueda de esta presa. En este trabajo se analizó el comportamiento de adultos de C. sanguinea expuestos a los semioquímicos volátiles, emitidos por sustratos de Capsicum annuum Linnaeus (Solanaceae sanos o infestados con Myzus persicae (Sulzer (Hemiptera: Aphididae, o simplemente puestos en contacto directo con esos sustratos. Los tratamientos evaluados fueron: A hojas de pimiento infestadas con alta densidad de áfidos, B hojas de pimiento infestadas con baja densidad de áfidos, C hojas de pimiento sanas y D control. La actividad locomotriz no difirió significativamente entre los distintos tratamientos cuando C. sanguinea se expuso solamente a los volátiles. En cambio, cuando los coccinélidos se pusieron en contacto directo con los sustratos evaluados, se encontraron diferencias significativas entre los tratamientos. Estos resultados preliminares indicarían que la sola presencia de un estímulo de olor, no sería suficiente para modular un patrón locomotor diferente en C. sanguinea.

  7. Optimal Active Vibration Suppression of Smart Composite Wind Turbine Blades

    Science.gov (United States)

    Abd El-Maksoud Mohamed, Sherif Ibrahim

    The purpose of this study is to apply active vibration control technique numerically for suppressing the vibrational level of a horizontal axis wind turbine blade. Two systems are studied to apply active vibration control on the wind turbine blade model, the first is a uniform cantilever beam and the other system is a non-uniform (tapered) cantilever beam. A single piezoelectric actuator and sensor are bonded on the upper and lower surface of the systems, respectively. The vibration analysis and dynamic characteristics of smart systems are obtained using approximate analytical methods. The entire structure is modeled in the state space form using the state space method, generalized coordinates and piezoelectric theory. Two types of controllers are designed to study the performance of the piezoelectric active controller. The first is a Proportional-Derivative (PD) controller and the other type is a Linear Quadratic Regulator (LQR). The Linear Quadratic Regulator (LQR) demonstrates better results for vibration suppression. The MATLAB code Simulink is used to simulate the different cases.

  8. Apamin suppresses biliary fibrosis and activation of hepatic stellate cells.

    Science.gov (United States)

    Kim, Jung-Yeon; An, Hyun-Jin; Kim, Woon-Hae; Park, Yoon-Yub; Park, Kyung Duck; Park, Kwan-Kyu

    2017-05-01

    Cholestatic liver disease is characterized by the progressive destruction of biliary epithelial cells (BECs) followed by fibrosis, cirrhosis and liver failure. Activated hepatic stellate cells (HSCs) and portal fibroblasts are the major cellular effectors of enhanced collagen deposition in biliary fibrosis. Apamin, an 18 amino acid peptide neurotoxin found in apitoxin (bee venom), is known to block Ca2+-activated K+ channels and prevent carbon tetrachloride-induced liver fibrosis. In the present study, we aimed to ascertain whether apamin inhibits biliary fibrosis and the proliferation of HSCs. Cholestatic liver fibrosis was established in mouse models with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) feeding. Cellular assays were performed on HSC-T6 cells (rat immortalized HSCs). DDC feeding led to increased hepatic damage and proinflammtory cytokine levels. Notably, apamin treatment resulted in decreased liver injury and proinflammatory cytokine levels. Moreover, apamin suppressed the deposition of collagen, proliferation of BECs and expression of fibrogenic genes in the DDC-fed mice. In HSCs, apamin suppressed activation of HSCs by inhibiting the Smad signaling pathway. These data suggest that apamin may be a potential therapeutic target in cholestatic liver disease.

  9. Locomotor activity of Phalerisida maculata Kulzer (Coleoptera, Tenebrionidae on Chilean sandy beaches Actividad locomotora de Phalerisida maculata Kulzer (Coleoptera, enebrionidae en playas arenosas chilenas

    Directory of Open Access Journals (Sweden)

    EDUARDO JARAMILLO

    2000-03-01

    Full Text Available The locomotor activity of the beetle Phalerisida maculata Kulzer (Coleoptera Tenebrionidae was studied on the surface of the substrate in two sandy beaches of the Chilean coast: one in north central (ca. 29ºS and the other in south central Chile (ca.39ºS. During the summer period of 1991 the circadian locomotor activity was studied in the southern beach, while during that of 1997 in both beaches. To analyze the activity, pitfall traps were used which were ordered along two transects extended between the upper beach and the resurgence zone. The traps were checked (i.e. collection of captured insects every two hours for a total period of 26 hours. The results showed that the adults of P. maculata were mostly active during the night hours, whereas the larvae were active during both, the day and night. Studies carried out in the beach located in south central Chile show that differences in the tidal range (neap vs. spring tides do not affect the activity patterns. During the locomotor activity, adult and larvae move to lower intertidal levels than those usually occupied while buried. Results of laboratory experiments using actographs under conditions of darkness and constant temperature, suggest that adults and larvae of P. maculata presented a circadian rhythm similar to that observed in the field experiments. It is concluded that P. maculata presents a behaviour that appear to be under control of an endogenous rhythm, without showing differences in the circadian rhythm of activity when beaches located at different latitudes are comparedSe estudió la actividad locomotriz del escarabajo Phalerisida maculata Kulzer (Coleoptera, Tenebrionidae sobre la superficie del sustrato de dos playas arenosas de la costa de Chile: una en el centro norte (ca. 29ºS y otra en el centro sur (ca. 39ºS. Durante el período estival de 1991 se estudió la actividad locomotriz circadiana en la playa del centro sur y durante el de 1997 en ambas playas. Para analizar

  10. [Suppression of cycling activity in sheep using parenteral progestagen treatment].

    Science.gov (United States)

    Janett, F; Camponovo, L; Lanker, U; Hässig, M; Thun, R

    2004-03-01

    The objective of this study was to evaluate the effect of two synthetic progestagen preparations Chlormadinone acetate (CAP, Chronosyn, Veterinaria AG Zürich) and Medroxyprogesterone acetate (MPA, Nadigest, G Streuli & Co. Uznach) on cycling activity and fertility in sheep. A flock of 28 non pregnant white alpine sheep was randomly divided into three groups, A (n = 10), B (n = 9) and C (n = 9). During a period of 4 weeks the cycling activity was confirmed by blood progesterone analysis. Thereafter, the animals of group A were treated with 50 mg CAP, those of group B with 140 mg MPA and those of group C with physiological saline solution. All injections were given intramuscularly. Suppression of endogenous progesterone secretion lasted from 28 to 49 days (mean = 39 days) in group A and from 42 to 70 days (mean = 50 days) in group B. The synchronization effect of both preparations was unsatisfactory as the occurrence of first estrus was distributed over a period of 3 weeks in group A and 4 weeks in group B. These findings could also be confirmed by the lambing period which lasted 52 days in group A and 36 days in group B. Control animals lambed within 9 days due to the synchronizing effect of the ram. The first fertile estrus was observed 36 days (group A) and 45 days (group B) after the treatment. In group A all 10 animals and in groups B and C 8 of 9 ewes each became pregnant. Parenteral progestagen application with CAP and MPA is a simple, safe and reversible method of estrus suppression in the sheep. The minimal suppressive duration of 4 (CAP) and 5 weeks (MPA) is not sufficient when a period of 3 months (alpine pasture period) is desired.

  11. Melatonin Inhibits Neural Cell Apoptosis and Promotes Locomotor Recovery via Activation of the Wnt/β-Catenin Signaling Pathway After Spinal Cord Injury.

    Science.gov (United States)

    Shen, Zhaoliang; Zhou, Zipeng; Gao, Shuang; Guo, Yue; Gao, Kai; Wang, Haoyu; Dang, Xiaoqian

    2017-08-01

    The spinal cord is highly sensitive to spinal cord injury (SCI) by external mechanical damage, resulting in irreversible neurological damage. Activation of the Wnt/β-catenin signaling pathway can effectively reduce apoptosis and protect against SCI. Melatonin, an indoleamine originally isolated from bovine pineal tissue, exerts neuroprotective effects after SCI through activation of the Wnt/β-catenin signaling pathway. In this study, we demonstrated that melatonin exhibited neuroprotective effects on neuronal apoptosis and supported functional recovery in a rat SCI model by activating the Wnt/β-catenin signaling pathway. We found that melatonin administration after SCI significantly upregulated the expression of low-density lipoprotein receptor related protein 6 phosphorylation (p-LRP-6), lymphoid enhancer factor-1 (LEF-1) and β-catenin protein in the spinal cord. Melatonin enhanced motor neuronal survival in the spinal cord ventral horn and improved the locomotor functions of rats after SCI. Melatonin administration after SCI also reduced the expression levels of Bax and cleaved caspase-3 in the spinal cord and the proportion of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) positive cells, but increased the expression level of Bcl-2. These results suggest that melatonin attenuated SCI by activating the Wnt/β-catenin signaling pathway.

  12. Omega-3 fatty acids from fish oil lower anxiety, improve cognitive functions and reduce spontaneous locomotor activity in a non-human primate.

    Directory of Open Access Journals (Sweden)

    Nina Vinot

    Full Text Available Omega-3 (ω3 polyunsaturated fatty acids (PUFA are major components of brain cells membranes. ω3 PUFA-deficient rodents exhibit severe cognitive impairments (learning, memory that have been linked to alteration of brain glucose utilization or to changes in neurotransmission processes. ω3 PUFA supplementation has been shown to lower anxiety and to improve several cognitive parameters in rodents, while very few data are available in primates. In humans, little is known about the association between anxiety and ω3 fatty acids supplementation and data are divergent about their impact on cognitive functions. Therefore, the development of nutritional studies in non-human primates is needed to disclose whether a long-term supplementation with long-chain ω3 PUFA has an impact on behavioural and cognitive parameters, differently or not from rodents. We address the hypothesis that ω3 PUFA supplementation could lower anxiety and improve cognitive performances of the Grey Mouse Lemur (Microcebus murinus, a nocturnal Malagasy prosimian primate. Adult male mouse lemurs were fed for 5 months on a control diet or on a diet supplemented with long-chain ω3 PUFA (n = 6 per group. Behavioural, cognitive and motor performances were measured using an open field test to evaluate anxiety, a circular platform test to evaluate reference spatial memory, a spontaneous locomotor activity monitoring and a sensory-motor test. ω3-supplemented animals exhibited lower anxiety level compared to control animals, what was accompanied by better performances in a reference spatial memory task (80% of successful trials vs 35% in controls, p<0.05, while the spontaneous locomotor activity was reduced by 31% in ω3-supplemented animals (p<0.001, a parameter that can be linked with lowered anxiety. The long-term dietary ω3 PUFA supplementation positively impacts on anxiety and cognitive performances in the adult mouse lemur. The supplementation of human food with ω3 fatty

  13. Involvement of the TRPV1 channel in the modulation of spontaneous locomotor activity, physical performance and physical exercise-induced physiological responses

    Directory of Open Access Journals (Sweden)

    A.S.R. Hudson

    2016-01-01

    Full Text Available Physical exercise triggers coordinated physiological responses to meet the augmented metabolic demand of contracting muscles. To provide adequate responses, the brain must receive sensory information about the physiological status of peripheral tissues and organs, such as changes in osmolality, temperature and pH. Most of the receptors involved in these afferent pathways express ion channels, including transient receptor potential (TRP channels, which are usually activated by more than one type of stimulus and are therefore considered polymodal receptors. Among these TRP channels, the TRPV1 channel (transient receptor potential vanilloid type 1 or capsaicin receptor has well-documented functions in the modulation of pain sensation and thermoregulatory responses. However, the TRPV1 channel is also expressed in non-neural tissues, suggesting that this channel may perform a broad range of functions. In this review, we first present a brief overview of the available tools for studying the physiological roles of the TRPV1 channel. Then, we present the relationship between the TRPV1 channel and spontaneous locomotor activity, physical performance, and modulation of several physiological responses, including water and electrolyte balance, muscle hypertrophy, and metabolic, cardiovascular, gastrointestinal, and inflammatory responses. Altogether, the data presented herein indicate that the TPRV1 channel modulates many physiological functions other than nociception and thermoregulation. In addition, these data open new possibilities for investigating the role of this channel in the acute effects induced by a single bout of physical exercise and in the chronic effects induced by physical training.

  14. Circadian changes in core body temperature, metabolic rate and locomotor activity in rats on a high-protein, carbohydrate-free diet.

    Science.gov (United States)

    Yamaoka, Ippei; Hagi, Mieko; Doi, Masako

    2009-12-01

    Ingestion of a high-protein meal results in body weight loss due to elevated energy expenditure, while also increasing satiety and decreasing subsequent food intake. The present study aimed to clarify the effects of a high-protein, carbohydrate-free diet (HPCFD) on these physiological indicators from a circadian perspective. Rats were given HPCFD or a pair-fed normal protein content diet (20% protein; NPD) for 4 d. The HPCFD group lost more body weight than the NPD group. Oxygen consumption (VO(2)) in the HPCFD group did not change during the experimental period, and tended to be higher during the light (L) phase than in the NPD group. Carbon dioxide production (VCO(2)) during the L phase was higher in the HPCFD group than in the NPD group, where VCO(2) was gradually decreased during the last dark (D) phase and throughout the L phase. The HPCFD group exhibited higher daily core body temperature (T(b)), particularly during the late D phase and throughout the L phase when compared to the NPD group. Locomotor activities during the D phase of the NPD group tended to gradually increase and were thus significantly higher than in the HPCFD group. These results suggest that HPCFD, even if energy intake is insufficient, maintains circadian changes in metabolic rates, resulting in maintenance of elevated daily T(b) and body weight reduction without increasing activity.

  15. Immune-suppressive activity of punicalagin via inhibition of NFAT activation

    International Nuclear Information System (INIS)

    Lee, Sang-Ik; Kim, Byoung-Soo; Kim, Kyoung-Shin; Lee, Samkeun; Shin, Kwang-Soo; Lim, Jong-Soon

    2008-01-01

    Since T cell activation is central to the development of autoimmune diseases, we screened a natural product library comprising 1400 samples of medicinal herbal extracts, to identify compounds that suppress T cell activity. Punicalagin (PCG) isolated from the fruit of Punica granatum was identified as a potent immune suppressant, based on its inhibitory action on the activation of the nuclear factor of activated T cells (NFAT). PCG downregulated the mRNA and soluble protein expression of interleukin-2 from anti-CD3/anti-CD28-stimulated murine splenic CD4+ T cells and suppressed mixed leukocytes reaction (MLR) without exhibiting cytotoxicity to the cells. In vivo, the PCG treatment inhibited phorbol 12-myristate 13-acetate (PMA)-induced chronic ear edema in mice and decreased CD3+ T cell infiltration of the inflamed tissue. These results suggest that PCG could be a potential candidate for the therapeutics of various immune pathologies

  16. Effects of Arc/Arg3.1 gene deletion on rhythmic synchronization of hippocampal CA1 neurons during locomotor activity and sleep.

    Science.gov (United States)

    Malkki, Hemi A I; Mertens, Paul E C; Lankelma, Jan V; Vinck, Martin; van Schalkwijk, Frank J; van Mourik-Donga, Laura B; Battaglia, Francesco P; Mahlke, Claudia; Kuhl, Dietmar; Pennartz, Cyriel M A

    2016-05-01

    The activity-regulated cytoskeletal-associated protein/activity regulated gene (Arc/Arg3.1) is crucial for long-term synaptic plasticity and memory formation. However, the neurophysiological substrates of memory deficits occurring in the absence of Arc/Arg3.1 are unknown. We compared hippocampal CA1 single-unit and local field potential (LFP) activity in Arc/Arg3.1 knockout and wild-type mice during track running and flanking sleep periods. Locomotor activity, basic firing and spatial coding properties of CA1 cells in knockout mice were not different from wild-type mice. During active behavior, however, knockout animals showed a significantly shifted balance in LFP power, with a relative loss in high-frequency (beta-2 and gamma) bands compared to low-frequency bands. Moreover, during track-running, knockout mice showed a decrease in phase locking of spiking activity to LFP oscillations in theta, beta and gamma bands. Sleep architecture in knockout mice was not grossly abnormal. Sharp-wave ripples, which have been associated with memory consolidation and replay, showed only minor differences in dynamics and amplitude. Altogether, these findings suggest that Arc/Arg3.1 effects on memory formation are not only manifested at the level of molecular pathways regulating synaptic plasticity, but also at the systems level. The disrupted power balance in theta, beta and gamma rhythmicity and concomitant loss of spike-field phase locking may affect memory encoding during initial storage and memory consolidation stages. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Serotonin 1A, 1B, and 7 receptors of the rat medial nucleus accumbens differentially regulate feeding, water intake, and locomotor activity.

    Science.gov (United States)

    Clissold, Kara A; Choi, Eugene; Pratt, Wayne E

    2013-11-01

    Serotonin (5-HT) signaling has been widely implicated in the regulation of feeding behaviors in both humans and animal models. Recently, we reported that co-stimulation of 5-HT1&7 receptors of the anterior medial nucleus accumbens with the drug 5-CT caused a dose-dependent decrease in food intake, water intake, and locomotion in rats (Pratt et al., 2009). The current experiments sought to determine which of three serotonin receptor subtypes (5-HT1A, 5-HT1B, or 5-HT7) might be responsible for these consummatory and locomotor effects. Food-deprived rats were given 2-h access to rat chow after stimulation of nucleus accumbens 5-HT1A, 5-HT1B, or 5-HT7 receptors, or blockade of the 5-HT1A or 5-HT1B receptors. Stimulation of 5-HT1A receptors with 8-OH-DPAT (at 0.0, 2.0, 4.0, and 8.0 μg/0.5 μl/side) caused a dose-dependent decrease in food and water intake, and reduced rearing behavior but not ambulation. In contrast, rats that received the 5-HT1B agonist CP 93129 (at 0.0, 1.0, 2.0 and 4.0 μg/0.5 μl/side) showed a significant dose-dependent decrease in water intake only; stimulation of 5-HT7 receptors (AS 19; at 0.0, 1.0, and 5.0 μg/0.5 μl/side) decreased ambulatory activity but did not affect food or water consumption. Blockade of 5-HT1A or 5-HT1B receptors had no lasting effects on measures of food consumption. These data suggest that the food intake, water intake, and locomotor effects seen after medial nucleus accumbens injections of 5-CT are due to actions on separate serotonin receptor subtypes, and contribute to growing evidence for selective roles of individual serotonin receptors within the nucleus accumbens on motivated behavior. © 2013.

  18. Covertly active and progressing neurochemical abnormalities in suppressed HIV infection.

    Science.gov (United States)

    Cysique, Lucette A; Jugé, Lauriane; Gates, Thomas; Tobia, Michael; Moffat, Kirsten; Brew, Bruce J; Rae, Caroline

    2018-01-01

    To assess whether HIV-related brain injury is progressive in persons with suppressed HIV infection. Seventy-three HIV+ virally suppressed men and 35 HIV- men, screened for psychiatric and alcohol/drug use disorders, underwent neuropsychological evaluation and proton magnetic resonance spectroscopy ( 1 H-MRS) at baseline and after and 23 ± 5 months. 1 H-MRS included brain regions known to be vulnerable to HIV and aging: frontal white matter (FWM), posterior cingulate cortex (PCC), and caudate area (CA). Major brain metabolites such as creatine (Cr: marker of cellular energy), N -acetyl aspartate (NAA: marker of neuronal integrity), choline (marker of cellular membrane turnover), glutamate/glutamine (excitatory/inhibitory neurotransmitter), and myo -Inositol (mI: marker of neuroinflammation) were calculated with reference to water signal. Neurocognitive decline was corrected for practice effect and baseline HIV-associated neurocognitive disorder (HAND) status. Across the study period, 44% had intact cognition, 42% stable HAND (including the single case that improved), 10% progressing HAND, and 4% incident HAND. When analyzing the neurochemical data per neurocognitive trajectories, we found decreasing PCC Cr in all subgroups compared with controls ( p < 0.002). In addition, relative to the HIV- group, stable HAND showed decreasing FWM Cr, incident HAND showed steep FWM Cr reduction, whereas progressing HAND had a sharply decreasing PCC NAA and reduced but stable CA NAA. When analyzing the neurochemical data at the group level (HIV+ vs HIV- groups), we found stable abnormal metabolite concentrations over the study period: decreased FWM and PCC Cr (both p < 0.001), decreased PCC NAA and CA NAA (both p < 0.05) and PCC mI increase ( p < 0.05). HIV duration and historical HAND had modest effects on metabolite changes. Our study reveals covertly active or progressing HIV-related brain injury in the majority of this virally suppressed cohort, reflecting ongoing

  19. Covertly active and progressing neurochemical abnormalities in suppressed HIV infection

    Science.gov (United States)

    Jugé, Lauriane; Gates, Thomas; Tobia, Michael; Moffat, Kirsten; Brew, Bruce J.; Rae, Caroline

    2018-01-01

    Objective To assess whether HIV-related brain injury is progressive in persons with suppressed HIV infection. Methods Seventy-three HIV+ virally suppressed men and 35 HIV− men, screened for psychiatric and alcohol/drug use disorders, underwent neuropsychological evaluation and proton magnetic resonance spectroscopy (1H-MRS) at baseline and after and 23 ± 5 months. 1H-MRS included brain regions known to be vulnerable to HIV and aging: frontal white matter (FWM), posterior cingulate cortex (PCC), and caudate area (CA). Major brain metabolites such as creatine (Cr: marker of cellular energy), N-acetyl aspartate (NAA: marker of neuronal integrity), choline (marker of cellular membrane turnover), glutamate/glutamine (excitatory/inhibitory neurotransmitter), and myo-Inositol (mI: marker of neuroinflammation) were calculated with reference to water signal. Neurocognitive decline was corrected for practice effect and baseline HIV-associated neurocognitive disorder (HAND) status. Results Across the study period, 44% had intact cognition, 42% stable HAND (including the single case that improved), 10% progressing HAND, and 4% incident HAND. When analyzing the neurochemical data per neurocognitive trajectories, we found decreasing PCC Cr in all subgroups compared with controls (p < 0.002). In addition, relative to the HIV− group, stable HAND showed decreasing FWM Cr, incident HAND showed steep FWM Cr reduction, whereas progressing HAND had a sharply decreasing PCC NAA and reduced but stable CA NAA. When analyzing the neurochemical data at the group level (HIV+ vs HIV− groups), we found stable abnormal metabolite concentrations over the study period: decreased FWM and PCC Cr (both p < 0.001), decreased PCC NAA and CA NAA (both p < 0.05) and PCC mI increase (p < 0.05). HIV duration and historical HAND had modest effects on metabolite changes. Conclusions Our study reveals covertly active or progressing HIV-related brain injury in the majority of this virally suppressed

  20. Assessment of long-range correlation in animal behavior time series: The temporal pattern of locomotor activity of Japanese quail (Coturnix coturnix) and mosquito larva (Culex quinquefasciatus)

    Science.gov (United States)

    Kembro, Jackelyn M.; Flesia, Ana Georgina; Gleiser, Raquel M.; Perillo, María A.; Marin, Raul H.

    2013-12-01

    Detrended Fluctuation Analysis (DFA) is a method that has been frequently used to determine the presence of long-range correlations in human and animal behaviors. However, according to previous authors using statistical model systems, in order to correctly use DFA different aspects should be taken into account such as: (1) the establishment by hypothesis testing of the absence of short term correlation, (2) an accurate estimation of a straight line in the log-log plot of the fluctuation function, (3) the elimination of artificial crossovers in the fluctuation function, and (4) the length of the time series. Taking into consideration these factors, herein we evaluated the presence of long-range correlation in the temporal pattern of locomotor activity of Japanese quail (Coturnix coturnix) and mosquito larva (Culex quinquefasciatus). In our study, modeling the data with the general autoregressive integrated moving average (ARFIMA) model, we rejected the hypothesis of short-range correlations (d=0) in all cases. We also observed that DFA was able to distinguish between the artificial crossover observed in the temporal pattern of locomotion of Japanese quail and the crossovers in the correlation behavior observed in mosquito larvae locomotion. Although the test duration can slightly influence the parameter estimation, no qualitative differences were observed between different test durations.

  1. Prenatal and early-life exposure to high-level diesel exhaust particles leads to increased locomotor activity and repetitive behaviors in mice.

    Science.gov (United States)

    Thirtamara Rajamani, Keerthi; Doherty-Lyons, Shannon; Bolden, Crystal; Willis, Daniel; Hoffman, Carol; Zelikoff, Judith; Chen, Lung-Chi; Gu, Howard

    2013-08-01

    Abundant evidence indicates that both genetic and environmental factors contribute to the etiology of autism spectrum disorders (ASDs). However, limited knowledge is available concerning these contributing factors. An epidemiology study reported a link between increased incidence of autism and living closely to major highways, suggesting a possible role for pollutants from highway traffic. We investigated whether maternal exposure to diesel exhaust particles (DEP) negatively affects fetal development leading to autism-like phenotype in mice. Female mice and their offspring were exposed to DEP during pregnancy and nursing. Adult male offspring were then tested for behaviors reflecting the typical symptoms of ASD patients. Compared to control mice, DEP-exposed offspring exhibited higher locomotor activity, elevated levels of self-grooming in the presence of an unfamiliar mouse, and increased rearing behaviors, which may be relevant to the restricted and repetitive behaviors seen in ASD patients. However, the DEP-exposed mice did not exhibit deficits in social interactions or social communication which are the key features of ASD. These results suggest that early life exposure to DEP could have an impact on mouse development leading to observable changes in animal behaviors. Further studies are needed to reveal other environmental insults and genetic factors that would lead to animal models expressing key phenotypes of the autism spectrum disorders. © 2013 International Society for Autism Research, Wiley Periodicals, Inc.

  2. Dmp53, basket and drICE gene knockdown and polyphenol gallic acid increase life span and locomotor activity in a Drosophila Parkinson's disease model

    Directory of Open Access Journals (Sweden)

    Hector Flavio Ortega-Arellano

    2013-01-01

    Full Text Available Understanding the mechanism(s by which dopaminergic (DAergic neurons are eroded in Parkinson's disease (PD is critical for effective therapeutic strategies. By using the binary tyrosine hydroxylase (TH-Gal4/UAS-X RNAi Drosophila melanogaster system, we report that Dmp53, basket and drICE gene knockdown in dopaminergic neurons prolong life span (p < 0.05; log-rank test and locomotor activity (p < 0.05; χ² test in D. melanogaster lines chronically exposed to (1 mM paraquat (PQ, oxidative stress (OS generator compared to untreated transgenic fly lines. Likewise, knockdown flies displayed higher climbing performance than control flies. Amazingly, gallic acid (GA significantly protected DAergic neurons, ameliorated life span, and climbing abilities in knockdown fly lines treated with PQ compared to flies treated with PQ only. Therefore, silencing specific gene(s involved in neuronal death might constitute an excellent tool to study the response of DAergic neurons to OS stimuli. We propose that a therapy with antioxidants and selectively "switching off" death genes in DAergic neurons could provide a means for pre-clinical PD individuals to significantly ameliorate their disease condition.

  3. Active Suppression of Narrowband Noise by Multiple Secondary Sources

    Directory of Open Access Journals (Sweden)

    Seokhoon Ryu

    2016-01-01

    Full Text Available This study presents theoretical and experimental investigation on the active suppression of narrowband noise with C1, C1.5, and C2 components by using multichannel secondary sources in a duct. The quality manipulation in the duct was controlled by changing quality factors which were incorporated into a multichannel FxLMS algorithm. The algorithm is extensively investigated in both theory and real-time control experiment. After analysing the primary and secondary paths of the duct system, an acoustic narrowband signal was chosen as a primary noise and the impulse responses were implemented as the secondary path models. Control results show that the quality factors in the algorithm that was implemented in a dSPACE 1104 provide a stable and excellent response compared to before control. It is obvious that the lower quality factor cancels the more primary noise as defined in the theory although the attenuation levels are not exactly and inversely proportional to the quality factor. The results in this study can be used for practical active sound quality control systems.

  4. Reversible suppression of sexual activity in tomcats with deslorelin implant.

    Science.gov (United States)

    Novotny, R; Cizek, P; Vitasek, R; Bartoskova, A; Prinosilova, P; Janosovska, M

    2012-09-01

    The aim of the study was to assess the efficacy of using a Gn-RH agonist implant (deslorelin, 4.7 mg, Suprelorin) to control sexual activity of male cats and reestablishment of sexual function after the implant removal 4 mo after placement. Using a control group (Group 1, n = 5), 22 domestic tomcats were given the implant subcutaneously in the region of the right shoulder blade and were then divided into two treatment groups. Animals in Group 2 (n = 14) were observed from the date of implant surgery and the observation lasted for 4 mo. In Group 3 (n = 8) all animals were monitored from the date of implant surgery. Then, after 4 mo, all implants were removed and the toms were observed for a further 4 mo. In all animals during their first visit and then in 1-mo intervals, changes in testosterone concentrations were assessed before (T0) and 4 h after (T4) human chorionic gonadotropin (HCG) administration and testis size was measured. In all tomcats, semen collection was performed, using an electroejaculator, in the course of the first visit and then in 2-mo intervals or at the end of observation. Total sperm count was determined in each semen sample. Two to four animals were castrated at weeks 4, 8, 12, 16, 20, 24, 28 and 32 and histologic assessment of the testes was performed. By evaluation of 200 cross sections of seminiferous tubules, the degree of spermatogenic suppression was assessed and animals in Groups 2 and 3 were assigned into groups according to most tubules with the most developed germ cell observed: G1, spermatocytes; G2, round spermatids; G3, elongating spermatids and G4, elongated spermatids. The mean area of Leydig-cell nuclei was calculated. In animals in Group 2, suppression after implant insertion was monitored. T4 concentrations, testis size, and total sperm count gradually decreased (P < 0.01; P < 0.01; and P < 0.05, respectively) within 4 mo after implantation. Histologic evaluation showed a high individual variation in the degree of

  5. Intra-articular intervention by hyaluronic acid for knee osteoarthritis can modify locomotor pattern of muscle activity.

    Science.gov (United States)

    Tang, Alice Chu-Wen; Hong, Wei-Hsien; Chen, Hsieh-Ching; Tang, Simon Fuk-Tan

    2015-02-01

    To evaluate the muscle activation pattern of lower extremities can be modified by intraarticular injection of hyaluronic acid( IAHA). Twenty-three subjects with knee OA and 14 age-matched non-knee OA control subjects were recruited from an outpatient clinic. Three-dimensional gait analysis with using the MA- 100 EMG system was applied to measure the muscles activities. The quadriceps (QUA), hamstrings (HAM), tibialis anterior (TA), and medial gastrocnemius (MG) muscles were selected for this study. For the knee OA group, bilateral IA knee joint injections with HA were performed. During the stance phase of gait cycle, the quadriceps, hamstring, and tibialis anterior muscles had longer muscle contraction duration in the knee OA patients as compared with the control group. The muscle activities of quadriceps, hamstrings, tibialis anterior, and medial gastrocnemius muscles recovered to a pattern similar to the control group after the completion of IA HA injections in knee OA patients. The H/Q ratio improved significantly after the IA HA injections, and also lasted up to a period of six months (p<0.01). IA HA is an available treatment option as it effectively decreases co-contraction and improves motor activity of the lower extremity muscles. The improved muscle activities lasted up to a period up to six months. © 2015 Elsevier B.V. All rights reserved.

  6. Distribution of networks generating and coordinating locomotor activity in the neonatal rat spinal cord in vitro: a lesion study

    DEFF Research Database (Denmark)

    Kjaerulff, O; Kiehn, O

    1996-01-01

    that the isolated ventral third of the spinal cord can generate normally coordinated rhythmic activity, whereas lateral fragments resulting from sagittal sections showed little or no rhythmogenic capability compared with intact control preparations. The ability to generate fast and regular rhythmic activity...... ventral root recordings to monitor neuronal activity and tested the ability of various isolated parts of the caudal thoraciclumbar cord to generate rhythmic bursting in a combination of 5-HT and NMDA. In addition, pathways mediating left/right and rostrocaudal burst alternation were localized. We found...... decreased in the caudal direction, but the rhythm-generating network was found to be distributed over the entire lumbar region and to extend into the caudal thoracic region. The pathways mediating left/ right alternation exist primarily in the ventral commissure. As with the rhythmogenic ability...

  7. Locomotor changes in length and EMG activity of feline medial gastrocnemius muscle following paralysis of two synergists

    NARCIS (Netherlands)

    Maas, H.; Gregor, R.J.; Hodson-Tole, E.F.; Farrell, B.J.; English, A.W.; Prilutsky, B.I.

    2010-01-01

    The mechanism of the compensatory increase in electromyographic activity (EMG) of a cat ankle extensor during walking shortly after paralysis of its synergists is not fully understood. It is possible that due to greater ankle Xexion in stance in this situation, muscle spindles are stretched to a

  8. Afferent contribution to locomotor muscle activity during unconstrained overground human walking: an analysis of triceps surae muscle fascicles

    DEFF Research Database (Denmark)

    Klint, Richard af; Cronin, Neil J.; Ishikawa, Masaki

    2010-01-01

    Plantar flexor series elasticity can be used to dissociate muscle fascicle and muscle tendon behaviour and, therefore, afferent feedback during human walking. We used electromyography (EMG) and high speed ultrasonography concomitantly to monitor muscle activity and muscle fascicle behaviour in ni...

  9. The Suppression of Star Formation by Powerful Active Galactic Nuclei

    Science.gov (United States)

    Dwek, E.

    2012-01-01

    The old, red stars that constitute the bulges of galaxies, and the massive black holes at their centres, are the relics of a period in cosmic history when galaxies formed stars at remarkable rates and active galactic nuclei (AGN) shone brightly as a result of accretion onto black holes. It is widely suspected, but unproved, that the tight corre1ation between the mass of the black hole and the mas. of the stellar bulge results from the AGN quenching the surrounding star formation as it approaches its peak luminosity. X-rays trace emission from AGN unambiguously, whereas powerful star-forming ga1axies are usually dust-obscured and are brightest at infrared and submillimeter wavelengths. Here we report submillimetre and X-ray observations that show that rapid star formation was common in the host galaxies of AGN when the Universe was 2-6 billion years old, but that the most vigorous star formation is not observed around black holes above an X-ray luminosity of 10(exp 44) ergs per second. This suppression of star formation in the host galaxy of a powerful AGN is a key prediction of models in which the AGN drives an outflow, expe11ing the interstellar medium of its host and transforming the galaxy's properties in a brief period of cosmic time.

  10. The suppression of star formation by powerful active galactic nuclei.

    Science.gov (United States)

    Page, M J; Symeonidis, M; Vieira, J D; Altieri, B; Amblard, A; Arumugam, V; Aussel, H; Babbedge, T; Blain, A; Bock, J; Boselli, A; Buat, V; Castro-Rodríguez, N; Cava, A; Chanial, P; Clements, D L; Conley, A; Conversi, L; Cooray, A; Dowell, C D; Dubois, E N; Dunlop, J S; Dwek, E; Dye, S; Eales, S; Elbaz, D; Farrah, D; Fox, M; Franceschini, A; Gear, W; Glenn, J; Griffin, M; Halpern, M; Hatziminaoglou, E; Ibar, E; Isaak, K; Ivison, R J; Lagache, G; Levenson, L; Lu, N; Madden, S; Maffei, B; Mainetti, G; Marchetti, L; Nguyen, H T; O'Halloran, B; Oliver, S J; Omont, A; Panuzzo, P; Papageorgiou, A; Pearson, C P; Pérez-Fournon, I; Pohlen, M; Rawlings, J I; Rigopoulou, D; Riguccini, L; Rizzo, D; Rodighiero, G; Roseboom, I G; Rowan-Robinson, M; Sánchez Portal, M; Schulz, B; Scott, D; Seymour, N; Shupe, D L; Smith, A J; Stevens, J A; Trichas, M; Tugwell, K E; Vaccari, M; Valtchanov, I; Viero, M; Vigroux, L; Wang, L; Ward, R; Wright, G; Xu, C K; Zemcov, M

    2012-05-09

    The old, red stars that constitute the bulges of galaxies, and the massive black holes at their centres, are the relics of a period in cosmic history when galaxies formed stars at remarkable rates and active galactic nuclei (AGN) shone brightly as a result of accretion onto black holes. It is widely suspected, but unproved, that the tight correlation between the mass of the black hole and the mass of the stellar bulge results from the AGN quenching the surrounding star formation as it approaches its peak luminosity. X-rays trace emission from AGN unambiguously, whereas powerful star-forming galaxies are usually dust-obscured and are brightest at infrared and submillimetre wavelengths. Here we report submillimetre and X-ray observations that show that rapid star formation was common in the host galaxies of AGN when the Universe was 2-6 billion years old, but that the most vigorous star formation is not observed around black holes above an X-ray luminosity of 10(44) ergs per second. This suppression of star formation in the host galaxy of a powerful AGN is a key prediction of models in which the AGN drives an outflow, expelling the interstellar medium of its host and transforming the galaxy's properties in a brief period of cosmic time.

  11. Prenatal ethanol exposure modifies locomotor activity and induces selective changes in Met-enk expression in adolescent rats.

    Science.gov (United States)

    Abate, P; Reyes-Guzmán, A C; Hernández-Fonseca, K; Méndez, M

    2017-04-01

    Several studies suggest that prenatal ethanol exposure (PEE) facilitates ethanol intake. Opioid peptides play a main role in ethanol reinforcement during infancy and adulthood. However, PEE effects upon motor responsiveness elicited by an ethanol challenge and the participation of opioids in these actions remain to be understood. This work assessed the susceptibility of adolescent rats to prenatal and/or postnatal ethanol exposure in terms of behavioral responses, as well as alcohol effects on Met-enk expression in brain areas related to drug reinforcement. Motor parameters (horizontal locomotion, rearings and stereotyped behaviors) in pre- and postnatally ethanol-challenged adolescents were evaluated. Pregnant rats received ethanol (2g/kg) or water during gestational days 17-20. Adolescents at postnatal day 30 (PD30) were tested in a three-trial activity paradigm (habituation, vehicle and drug sessions). Met-enk content was quantitated by radioimmunoassay in several regions: ventral tegmental area [VTA], nucleus accumbens [NAcc], prefrontal cortex [PFC], substantia nigra [SN], caudate-putamen [CP], amygdala, hypothalamus and hippocampus. PEE significantly reduced rearing responses. Ethanol challenge at PD30 decreased horizontal locomotion and showed a tendency to reduce rearings and stereotyped behaviors. PEE increased Met-enk content in the PFC, CP, hypothalamus and hippocampus, but did not alter peptide levels in the amygdala, VTA and NAcc. These findings suggest that PEE selectively modifies behavioral parameters at PD30 and induces specific changes in Met-enk content in regions of the mesocortical and nigrostriatal pathways, the hypothalamus and hippocampus. Prenatal and postnatal ethanol actions on motor activity in adolescents could involve activation of specific neural enkephalinergic pathways. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. The effects of exercise on cocaine self-administration, food-maintained responding, and locomotor activity in female rats: importance of the temporal relationship between physical activity and initial drug exposure.

    Science.gov (United States)

    Smith, Mark A; Witte, Maryam A

    2012-12-01

    Previous studies have reported that exercise decreases cocaine self-administration in rats with long-term access (8+ weeks) to activity wheels in the home cage. The purpose of this study was to (a) examine the importance of the temporal relationship between physical activity and initial drug exposure, (b) determine the effects of exercise on responding maintained by a nondrug reinforcer (i.e., food), and (c) investigate the effects of exercise on cocaine-induced increases in locomotor activity. To this end, female rats were obtained at weaning and divided into 4 groups: (a) EXE-SED rats were housed in exercise cages for 6 weeks and then transferred to sedentary cages after the first day of behavioral testing; (b) SED-EXE rats were housed in sedentary cages for 6 weeks and then transferred to exercise cages after the first day of behavioral testing; (c) SED-SED rats remained in sedentary cages for the duration of the study; and (d) EXE-EXE rats remained in exercise cages for the duration of the study. Relative to the sedentary group (SED-SED), exercise reduced cocaine self-administration in both groups with access to activity wheels after initial drug exposure (EXE-EXE, SED-EXE) but did not reduce cocaine self-administration in the group with access to activity wheels only before drug exposure (EXE-SED). Exercise also decreased the effects of cocaine on locomotor activity but did not reduce responding maintained by food. These data suggest that exercise may reduce cocaine use in drug-experienced individuals with no prior history of aerobic activity without decreasing other types of positively reinforced behaviors.

  13. Pain-inhibiting inhomogeneous static magnetic field fails to influence locomotor activity and anxiety behavior in mice: no interference between magnetic field- and morphine-treatment.

    Science.gov (United States)

    László, János; Tímár, Júlia; Gyarmati, Zsuzsanna; Fürst, Zsuzsanna; Gyires, Klára

    2009-06-30

    We wanted to demonstrate (i) in the writhing test in mice, whether there was a prolonged analgesic effect induced by an inhomogeneous static magnetic field (SMF) exposure; (ii) whether SMF had an effect on the analgesic effect induced by 0.5mg/kgs.c. administered morphine, on the behavioral patterns, and on the hyperlocomotion-inducing effect of morphine. A magnetic exposure system developed by the present authors was used with peak-to-peak flux densities in the 2-754mT range. The writhing test was used for the assessment of pain. An elevated plus maze and a Conducta System was used for studying the anxiogenic or anxyolitic effect in mice, and the locomotor activity, respectively. We looked for the difference in the number of writhings and in the behavioral patterns between treated (s.c. morphine and/or SMF exposure) and control animals, respectively. (i) The antinociceptive effect could be identified 10-30min following SMF exposition in the writhing test in mice. (ii) SMF failed to affect the morphine-induced antinociception, the behavioral patterns in either type of tests, and the hyperlocomotion-inducing effect of morphine. (i) The long-lasting antinociceptive effect of SMF allows experiments under conditions, when in situ application of the SMF-producing device would be technically difficult or impossible; or where it would disturb the experiments. (ii) The results of behavioral tests with freely moving mice in or in the vicinity of inhomogeneous SMFs are not affected by the SMF in the applied flux density range. (iii) Morphine in treated subjects is not interacting with the inhomogeneous SMFs in the applied flux density range.

  14. Capacity of novelty-induced locomotor activity and the hole-board test to predict sensitivity to the conditioned rewarding effects of cocaine.

    Science.gov (United States)

    Arenas, M Carmen; Daza-Losada, Manuel; Vidal-Infer, Antonio; Aguilar, Maria A; Miñarro, José; Rodríguez-Arias, Marta

    2014-06-22

    Novelty-seeking in rodents, defined as enhanced specific exploration of novel situations, is considered to predict the response of animals to drugs of abuse and, thus, allow "drug-vulnerable" individuals to be identified. The main objective of this study was to assess the predictive ability of two well-known paradigms of the novelty-seeking trait - novelty-induced locomotor activity (which distinguishes High- and Low-Responder mice, depending on their motor activity) and the hole-board test (which determines High- and Low-Novelty Seeker mice depending on the number of head dips they perform) - to identify subjects that would subsequently be more sensitive to the conditioned rewarding effects of cocaine in a population of young adult (PND 56) and adolescent (PND 35) OF1 mice of both sexes. Conditioned place preference (CPP), a useful tool for evaluating the sensitivity of individuals to the incentive properties of addictive drugs, was induced with a sub-threshold dose of cocaine (1 mg/kg, i.p.). Our results showed that novelty-induced motor activity had a greater predictive capacity to identify "vulnerable-drug" individuals among young-adult mice (PND 56), while the hole-board test was more effective in adolescents (PND 35). High-NR young-adults, which presented higher motor activity in the first ten minutes of the test (novelty-reactivity), were 3.9 times more likely to develop cocaine-induced CPP than Low-NR young-adults. When total activity (1h) was evaluated (novelty-habituation), only High-R (novelty-non-habituating) young-adult male and Low-R (novelty-habituating) female mice produced a high conditioning score. However, only High-Novelty Seeker male and female adolescents and Low-Novelty Seeker female young-adult animals (according to the hole-board test), acquired cocaine-induced CPP. These findings should contribute to the development of screening methods for identifying at-risk human drug users and prevention strategies for those with specific

  15. Technical Actions, Heart Rate, and Locomotor Activity in 7v7 and 8v8 Games for Female Youth Soccer Players.

    Science.gov (United States)

    Ørntoft, Christina; Larsen, Malte N; Andersen, Thomas B; Rasmussen, Lasse S; Póvoas, Susana C A; Randers, Morten B; Krustrup, Peter

    2016-12-01

    Ørntoft, C, Larsen, MN, Andersen, TB, Rasmussen, LS, Póvoas, SCA, Randers, MB, and Krustrup, P. Technical actions, heart rate, and locomotor activity in 7v7 and 8v8 games for female youth soccer players. J Strength Cond Res 30(12): 3298-3303, 2016-The purpose of this study was to evaluate technical performance, heart rate (HR), and activity profile in 7v7 and 8v8 soccer games for 9- to 10-year-old girls (U11). A total of 24 female youth players participated in the study, all playing 20-minute 7v7 and 8v8 games with 160 and 223 m per player, respectively. Technical actions, HR, and activity profile were measured during the games using video filming, HR monitors, and 5-Hz Global positioning system (GPS) units. The number of technical actions was higher in 7v7 than in 8v8 games (34 ± 19 vs. 28 ± 14; p = 0.03; d = 0.37), as was the number of successful actions (25 ± 16 vs. 20 ± 12; p = 0.01; d = 0.35), with no difference in success rate for technical actions (70 ± 13 vs. 69 ± 14%; p = 0.63; d = 0.07). No differences were found between 7v7 and 8v8 in total distance covered (1,574 ± 251 and 1,622 ± 281 m; p = 0.66; d = 0.18), peak speed (19.5 ± 2.6 and 20.7 ± 1.5 km·h; p = 0.16; d = 0.56), mean HR values (85 ± 5 and 86 ± 6%HRpeak; p = 0.85; d = 0.18), and time of >90% HRpeak (37 ± 16 and 35 ± 14% of playing time; p = 0.70; d = 0.13). Distance covered at the highest running speeds of >16 km·h was lower in 7v7 than in 8v8 games (34 ± 24 vs. 63 ± 34 m; p = 0.018; d = 0.98), as was the number of entries into this speed zone (8 ± 5 vs. 13 ± 7; p = 0.006; d = 0.82). In conclusion, more technical actions and successful actions were observed in 7v7 than in 8v8 games, but players covered more ground with high-speed running in 8v8 games. This study also revealed that HR values were high in both game formats for U11 adolescent female players, with no difference between formats.

  16. Intermedin suppresses pressure overload cardiac hypertrophy through activation of autophagy.

    Science.gov (United States)

    Chen, Huali; Wang, Xue; Tong, Mingming; Wu, Dan; Wu, Sisi; Chen, Jiaxiang; Wang, Xiaoxiao; Wang, Xulei; Kang, Yu; Tang, Hong; Tang, Chaoshu; Jiang, Wei

    2013-01-01

    Left ventricular hypertrophy is a maladaptive response to pressure overload and an important risk factor for heart failure. Intermedin (IMD), a multi-functional peptide, plays important roles in cardiovascular protection. In this study, we revealed an autophagy-dependent mechanism involved in IMD's protection against cardiac remodeling and cardiomyocyte death in heart hypertrophy. We observed that transverse aortic contraction (TAC) induction, Ang II or ISO exposure induced remarkable increase in the expression of endogenous IMD and its receptor components, CRLR, RAMP1 and RAMP3, in mouse hearts and H9c2 cell cultures, respectively. Furthermore, the heart size, heart weight/body weight ratios, cardiomyocyte size and apoptosis, interstitial collagen, hypertrophic markers including ANP and BNP expression were also significantly increased, which were effectively suppressed by IMD supplementation. In addition, IMD induced capillary angiogenesis and improved functions in hypertrophic hearts. We further observed that IMD induced strong autophagy in hypertrophic hearts and cultured cells, which was paralleling with the decrease in cardiomyocyte size and apoptosis. Furthermore, an autophagy inhibitor, 3-MA, was used to block the IMD-augmented autophagy level, and then the protection of IMD on cardiomyocyte hypertrophy and apoptosis was almost abrogated. We also observed that IMD supplementation stirred intracellular cAMP production, and augmented the ERK1/2 phosphorylation induced by Ang II/ISO exposure in H9c2 cells. In addition, we inhibited PI3K, PKA and MAPK/ERK1/2 signaling pathways by using wortamannin, H89 and PD98059, respectively, in H9c2 cells co-incubating with both IMD and Ang II or ISO, and observed that these inhibitors effectively reduced IMD-augmented autophagy level, but only H89 and PD98059 pre-incubation abrogated the anti-apoptotic action of IMD. These results indicate that the endogenous IMD and its receptor complexes are induced in hypertrophic

  17. Intermedin suppresses pressure overload cardiac hypertrophy through activation of autophagy.

    Directory of Open Access Journals (Sweden)

    Huali Chen

    Full Text Available Left ventricular hypertrophy is a maladaptive response to pressure overload and an important risk factor for heart failure. Intermedin (IMD, a multi-functional peptide, plays important roles in cardiovascular protection. In this study, we revealed an autophagy-dependent mechanism involved in IMD's protection against cardiac remodeling and cardiomyocyte death in heart hypertrophy. We observed that transverse aortic contraction (TAC induction, Ang II or ISO exposure induced remarkable increase in the expression of endogenous IMD and its receptor components, CRLR, RAMP1 and RAMP3, in mouse hearts and H9c2 cell cultures, respectively. Furthermore, the heart size, heart weight/body weight ratios, cardiomyocyte size and apoptosis, interstitial collagen, hypertrophic markers including ANP and BNP expression were also significantly increased, which were effectively suppressed by IMD supplementation. In addition, IMD induced capillary angiogenesis and improved functions in hypertrophic hearts. We further observed that IMD induced strong autophagy in hypertrophic hearts and cultured cells, which was paralleling with the decrease in cardiomyocyte size and apoptosis. Furthermore, an autophagy inhibitor, 3-MA, was used to block the IMD-augmented autophagy level, and then the protection of IMD on cardiomyocyte hypertrophy and apoptosis was almost abrogated. We also observed that IMD supplementation stirred intracellular cAMP production, and augmented the ERK1/2 phosphorylation induced by Ang II/ISO exposure in H9c2 cells. In addition, we inhibited PI3K, PKA and MAPK/ERK1/2 signaling pathways by using wortamannin, H89 and PD98059, respectively, in H9c2 cells co-incubating with both IMD and Ang II or ISO, and observed that these inhibitors effectively reduced IMD-augmented autophagy level, but only H89 and PD98059 pre-incubation abrogated the anti-apoptotic action of IMD. These results indicate that the endogenous IMD and its receptor complexes are induced in

  18. Anti-cocaine antibody and butyrylcholinesterase-derived cocaine hydrolase exert cooperative effects on cocaine pharmacokinetics and cocaine-induced locomotor activity in mice

    OpenAIRE

    Brimijoin, Stephen; Orson, Frank; Kosten, Tom; Kinsey, Berma; Shen, Xiao Yun; White, Sarah J.; Gao, Yang

    2012-01-01

    We are investigating treatments for cocaine abuse based on viral gene transfer of a cocaine hydrolase (CocH) derived from human butyrylcholinesterase, which can reduce cocaine-stimulated locomotion and cocaine-primed reinstatement of drug-seeking behavior in rats for many months. Here, in mice, we explored the possibility that anti-cocaine antibodies can complement the actions of CocH to reduce cocaine uptake in brain and block centrally-evoked locomotor stimulation. Direct injections of test...

  19. The roles of 5-HT1A and 5-HT2 receptors in the effects of 5-MeO-DMT on locomotor activity and prepulse inhibition in rats.

    Science.gov (United States)

    Krebs-Thomson, Kirsten; Ruiz, Erbert M; Masten, Virginia; Buell, Mahalah; Geyer, Mark A

    2006-12-01

    The hallucinogen 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is structurally similar to other indoleamine hallucinogens such as LSD. The present study examined the effects of 5-MeO-DMT in rats using the Behavioral Pattern Monitor (BPM), which enables analyses of patterns of locomotor activity and exploration, and the prepulse inhibition of startle (PPI) paradigm. A series of interaction studies using the serotonin (5-HT)(1A) antagonist WAY-100635 (1.0 mg/kg), the 5-HT(2A) antagonist M100907 (1.0 mg/kg), and the 5-HT(2C) antagonist SER-082 (0.5 mg/kg) were performed to assess the respective contributions of these receptors to the behavioral effects of 5-MeO-DMT (0.01, 0.1, and 1.0 mg/kg) in the BPM and PPI paradigms. 5-MeO-DMT decreased locomotor activity, investigatory behavior, the time spent in the center of the BPM chamber, and disrupted PPI. All of these effects were antagonized by WAY-100635 pretreatment. M100907 pretreatment failed to attenuate any of these effects, while SER-082 pretreatment only antagonized the PPI disruption produced by 5-MeO-DMT. While the prevailing view was that the activation of 5-HT(2) receptors is solely responsible for hallucinogenic drug effects, these results support a role for 5-HT(1A) receptors in the effects of the indoleamine hallucinogen 5-MeO-DMT on locomotor activity and PPI in rats.

  20. Divergent effect of the selective D3 receptor agonist pd-128,907 on locomotor activity in Roman high- and low-avoidance rats: relationship to NGFI-A gene expression in the Calleja islands.

    Science.gov (United States)

    Guitart-Masip, Marc; Johansson, Björn; Fernández-Teruel, Albert; Tobeña, Adolf; Giménez-Llort, Lydia

    2008-01-01

    The inbred Roman high- (RHA-I) and low-avoidance (RLA-I) rats, differing in dopaminergic activity and novelty/substance-seeking profiles, may be a suitable model to study the implication of the dopaminergic system in vulnerability to drug abuse. Differences in D3 receptor binding recently described between the two strains (Guitart-Masip M, Johansson B, Fernández-Teruel A, Cañete T, Tobeña A, Terenius L, Giménez-Llort L, Neuroscience 142:1231-1243, 2006b) may be important in shaping the aforementioned differences in novelty seeking. The aim of the present work was to study the effect of D3 receptor activation on novelty-induced locomotor activity in these two strains of rats. We administered saline and PD-128,907 (0.01 and 0.1 mg/kg), a putative D3 receptor agonist, to the Roman rats and studied the locomotor activity when animals were placed in a novel environment. Thereafter, by means of in situ hybridization, nerve growth factor inducible clone A (NGFI-A) mRNA was measured in the striatum and the Calleja islands of these animals. We found that RLA-I rats showed stronger locomotor inhibition than RHA-I rats after PD-128,907 administration. Moreover, RLA-I rats showed stronger reduction of NGFI-A mRNA in the Calleja islands than RHA-I rats. These results, together with previous findings, suggest that differences in D3 receptor expression in the Calleja islands may contribute to the divergent behavioral effect of PD-128,907 administration in the two strains of Roman rats.

  1. HMGB1 enhances immune suppression by facilitating the differentiation and suppressive activity of myeloid-derived suppressor cells.

    Science.gov (United States)

    Parker, Katherine H; Sinha, Pratima; Horn, Lucas A; Clements, Virginia K; Yang, Huan; Li, Jianhua; Tracey, Kevin J; Ostrand-Rosenberg, Suzanne

    2014-10-15

    Chronic inflammation often precedes malignant transformation and later drives tumor progression. Likewise, subversion of the immune system plays a role in tumor progression, with tumoral immune escape now well recognized as a crucial hallmark of cancer. Myeloid-derived suppressor cells (MDSC) are elevated in most individuals with cancer, where their accumulation and suppressive activity are driven by inflammation. Thus, MDSCs may define an element of the pathogenic inflammatory processes that drives immune escape. The secreted alarmin HMGB1 is a proinflammatory partner, inducer, and chaperone for many proinflammatory molecules that MDSCs develop. Therefore, in this study, we examined HMGB1 as a potential regulator of MDSCs. In murine tumor systems, HMGB1 was ubiquitous in the tumor microenvironment, activating the NF-κB signal transduction pathway in MDSCs and regulating their quantity and quality. We found that HMGB1 promotes the development of MDSCs from bone marrow progenitor cells, contributing to their ability to suppress antigen-driven activation of CD4(+) and CD8(+) T cells. Furthermore, HMGB1 increased MDSC-mediated production of IL-10, enhanced crosstalk between MDSCs and macrophages, and facilitated the ability of MDSCs to downregulate expression of the T-cell homing receptor L-selectin. Overall, our results revealed a pivotal role for HMGB1 in the development and cancerous contributions of MDSCs. ©2014 American Association for Cancer Research.

  2. Effects of noradrenaline on locomotor rhythm-generating networks in the isolated neonatal rat spinal cord

    DEFF Research Database (Denmark)

    Kiehn, O; Sillar, K T; Kjaerulff, O

    1999-01-01

    , the addition of NA to the NMDA/5-HT saline could reinstate a well-coordinated locomotor rhythm. We conclude that exogenously applied NA can elicit tonic activity or can trigger a slow, irregular and often synchronous motor pattern. When NA is applied during ongoing locomotor activity, the amine has a distinct...

  3. Adenosine kinase inhibitors: polar 7-substitutent of pyridopyrimidine derivatives improving their locomotor selectivity.

    Science.gov (United States)

    Zheng, Guo Zhu; Mao, Yue; Lee, Chih-Hung; Pratt, John K; Koenig, John R; Perner, Richard J; Cowart, Marlon D; Gfesser, Gregory A; McGaraughty, Steve; Chu, Katharine L; Zhu, Chang; Yu, Haixia; Kohlhaas, Kathy; Alexander, Karen M; Wismer, Carol T; Mikusa, Joseph; Jarvis, Michael F; Kowaluk, Elizabeth A; Stewart, Andrew O

    2003-09-15

    We have discovered that polar 7-substituents of pyridopyrimidine derivatives affect not only whole cell AK inhibitory potency, but also selectivity in causing locomotor side effects in vivo animal models. We have identified compound, 1o, which has potent whole cell AK inhibitory potency, analgesic activity and minimal reduction of locomotor activity.

  4. Enhanced effects of amphetamine but reduced effects of the hallucinogen, 5-MeO-DMT, on locomotor activity in 5-HT1A receptor knockout mice: Implications for schizophrenia

    Science.gov (United States)

    van den Buuse, Maarten; Ruimschotel, Emma; Martin, Sally; Risbrough, Victoria B.; Halberstadt, Adam L.

    2012-01-01

    Serotonin-1A (5-HT1A) receptors may play a role in schizophrenia and the effects of certain antipsychotic drugs. However, the mechanism of interaction of 5-HT1A receptors with brain systems involved in schizophrenia, remains unclear. Here we show that 5-HT1A receptor knockout mice display enhanced locomotor hyperactivity to acute treatment with amphetamine, a widely used animal model of hyperdopaminergic mechanisms in psychosis. In contrast, the effect of MK-801 on locomotor activity, modeling NMDA receptor hypoactivity, was unchanged in the knockouts. The effect of the hallucinogen 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) was markedly reduced in 5-HT1A receptor knockout mice. There were no changes in apomorphine-induced disruption of PPI, a model of sensory gating deficits seen in schizophrenia. Similarly, there were no major changes in density of dopamine transporters (DAT) or dopamine D1 or D2 receptors which could explain the behavioural changes observed in 5-HT1A receptor knockout mice. These results extend our insight into the possible role of these receptors in aspects of schizophrenia. As also suggested by previous studies using agonist and antagonist drugs, 5-HT1A receptors may play an important role in hallucinations and to modulate dopaminergic activity in the brain. PMID:21501627

  5. Enhanced effects of amphetamine but reduced effects of the hallucinogen, 5-MeO-DMT, on locomotor activity in 5-HT(1A) receptor knockout mice: implications for schizophrenia.

    Science.gov (United States)

    van den Buuse, Maarten; Ruimschotel, Emma; Martin, Sally; Risbrough, Victoria B; Halberstadt, Adam L

    2011-01-01

    Serotonin-1A (5-HT(1A)) receptors may play a role in schizophrenia and the effects of certain antipsychotic drugs. However, the mechanism of interaction of 5-HT(1A) receptors with brain systems involved in schizophrenia, remains unclear. Here we show that 5-HT(1A) receptor knockout mice display enhanced locomotor hyperactivity to acute treatment with amphetamine, a widely used animal model of hyperdopaminergic mechanisms in psychosis. In contrast, the effect of MK-801 on locomotor activity, modeling NMDA receptor hypoactivity, was unchanged in the knockouts. The effect of the hallucinogen 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) was markedly reduced in 5-HT(1A) receptor knockout mice. There were no changes in apomorphine-induced disruption of PPI, a model of sensory gating deficits seen in schizophrenia. Similarly, there were no major changes in density of dopamine transporters (DAT) or dopamine D(1) or D(2) receptors which could explain the behavioural changes observed in 5-HT(1A) receptor knockout mice. These results extend our insight into the possible role of these receptors in aspects of schizophrenia. As also suggested by previous studies using agonist and antagonist drugs, 5-HT(1A) receptors may play an important role in hallucinations and to modulate dopaminergic activity in the brain. Copyright © 2011 Elsevier Ltd. All rights reserved.

  6. Platelet activating factor receptor binding plays a critical role in jet fuel-induced immune suppression

    International Nuclear Information System (INIS)

    Ramos, Gerardo; Kazimi, Nasser; Nghiem, Dat X.; Walterscheid, Jeffrey P.; Ullrich, Stephen E.

    2004-01-01

    Applying military jet fuel (JP-8) or commercial jet fuel (Jet-A) to the skin of mice suppresses the immune response in a dose-dependant manner. The release of biological response modifiers, particularly prostaglandin E 2 (PGE 2 ), is a critical step in activating immune suppression. Previous studies have shown that injecting selective cyclooxygenase-2 inhibitors into jet fuel-treated mice blocks immune suppression. Because the inflammatory phospholipid mediator, platelet-activating factor (PAF), up-regulates cyclooxygenase-2 production and PGE 2 synthesis by keratinocytes, we tested the hypothesis that PAF-receptor binding plays a role in jet fuel-induced immune suppression. Treating keratinocyte cultures with PAF and/or jet fuel (JP-8 and Jet-A) stimulates PGE 2 secretion. Jet fuel-induced PGE 2 production was suppressed by treating the keratinocytes with specific PAF-receptor antagonists. Injecting mice with PAF, or treating the skin of the mice with JP-8, or Jet-A, induced immune suppression. Jet fuel-induced immune suppression was blocked when the jet fuel-treated mice were injected with PAF-receptor antagonists before treatment. Jet fuel treatment has been reported to activate oxidative stress and treating the mice with anti-oxidants (Vitamins C, or E or beta-hydroxy toluene), before jet fuel application, interfered with immune suppression. These findings confirm previous studies showing that PAF-receptor binding can modulate immune function. Furthermore, they suggest that PAF-receptor binding may be an early event in the induction of immune suppression by immunotoxic environmental agents that target the skin

  7. Active Suppression of Drilling System Vibrations For Deep Drilling

    Energy Technology Data Exchange (ETDEWEB)

    Raymond, David W.; Blankenship, Douglas A.; Buerger, Stephen; Mesh, Mikhail; Radigan, William Thomas; Su, Jiann-Cherng

    2015-10-01

    The dynamic stability of deep drillstrings is challenged by an inability to impart controllability with ever-changing conditions introduced by geology, depth, structural dynamic properties and operating conditions. A multi-organizational LDRD project team at Sandia National Laboratories successfully demonstrated advanced technologies for mitigating drillstring vibrations to improve the reliability of drilling systems used for construction of deep, high-value wells. Using computational modeling and dynamic substructuring techniques, the benefit of controllable actuators at discrete locations in the drillstring is determined. Prototype downhole tools were developed and evaluated in laboratory test fixtures simulating the structural dynamic response of a deep drillstring. A laboratory-based drilling applicability demonstration was conducted to demonstrate the benefit available from deployment of an autonomous, downhole tool with self-actuation capabilities in response to the dynamic response of the host drillstring. A concept is presented for a prototype drilling tool based upon the technical advances. The technology described herein is the subject of U.S. Patent Application No. 62219481, entitled "DRILLING SYSTEM VIBRATION SUPPRESSION SYSTEMS AND METHODS", filed September 16, 2015.

  8. Active vertical tail buffeting suppression based on macro fiber composites

    Science.gov (United States)

    Zou, Chengzhe; Li, Bin; Liang, Li; Wang, Wei

    2016-04-01

    Aerodynamic buffet is unsteady airflow exerting forces onto a surface, which can lead to premature fatigue damage of aircraft vertical tail structures, especially for aircrafts with twin vertical tails at high angles of attack. In this work, Macro Fiber Composite (MFC), which can provide strain actuation, was used as the actuator for the buffet-induced vibration control, and the positioning of the MFC patches was led by the strain energy distribution on the vertical tail. Positive Position Feedback (PPF) control algorithm has been widely used for its robustness and simplicity in practice, and consequently it was developed to suppress the buffet responses of first bending and torsional mode of vertical tail. However, its performance is usually attenuated by the phase contributions from non-collocated sensor/actuator configuration and plants. The phase lag between the input and output signals of the control system was identified experimentally, and the phase compensation was considered in the PPF control algorithm. The simulation results of the amplitude frequency of the closed-loop system showed that the buffet response was alleviated notably around the concerned bandwidth. Then the wind tunnel experiment was conducted to verify the effectiveness of MFC actuators and compensated PPF, and the Root Mean Square (RMS) of the acceleration response was reduced 43.4%, 28.4% and 39.5%, respectively, under three different buffeting conditions.

  9. Extinction cross-section suppression and active acoustic invisibility cloaking

    Science.gov (United States)

    Mitri, F. G.

    2017-10-01

    Invisibility in its canonical form requires rendering a zero extinction cross-section (or energy efficiency) from an active or a passive object. This work demonstrates the successful theoretical realization of this physical effect for an active cylindrically radiating acoustic body, undergoing periodic axisymmetric harmonic vibrations near a flat rigid boundary. Radiating, amplification and extinction cross-sections of the active source are defined. Assuming monopole and dipole modal oscillations of the circular source, conditions are found where the extinction energy efficiency factor of the active source vanishes, achieving total invisibility with minimal influence of the source size. It also takes positive or negative values, depending on its size and distance from the boundary. Moreover, the amplification energy efficiency factor is negative for the acoustically-active source. These effects also occur for higher-order modal oscillations of the active source. The results find potential applications in the development of acoustic cloaking devices and invisibility.

  10. Exposição repetida à cafeína aumenta a atividade locomotora induzida pelo femproporex em ratos adolescentes e adultos Repeated administration of caffeine increases femproporex-induced locomotor activity in adolescent and adult rats

    Directory of Open Access Journals (Sweden)

    Ana Helena Paro

    2008-09-01

    Full Text Available A cafeína e o femproporex são substâncias psicoestimulantes. O femproporex é muito utilizado no Brasil como anorexígeno enquanto a cafeína é amplamente consumida como constituinte regular da dieta. A administração repetida de psicoestimulantes induz sensibilização comportamental que se caracteriza pelo aumento progressivo dos seus efeitos locomotores. Pode ocorrer ainda sensibilização cruzada entre essas substâncias. Investigamos se a administração repetida de cafeína aumenta a locomoção induzida pelo femproporex em ratos adolescentes e adultos. Quarenta e oito ratos adolescentes (dia pós-natal 27 e 32 adultos (dia pós-natal 60 foram distribuídos em dois grupos que receberam injeção intra-peritoneal de 10,0 mg/kg de cafeína (CAF (adolescentes N = 24; adultos N = 16 ou salina (SAL (adolescentes N = 24; adultos N = 16 diariamente durante 10 dias. Três dias após a última injeção, cada grupo CAF ou SAL foi subdividido em dois subgrupos que receberam injeção i.p. de salina (SAL (1 mL/kg ou femproporex (FEM (2,0 mg/kg. Após as injeções, a atividade locomotora foi avaliada automaticamente em intervalos de 5 minutos durante 1 hora. Nossos resultados demonstraram que em ratos adolescentes e adultos o pré-tratamento com CAF aumenta a atividade locomotora induzida pela administração aguda de FEM, sugerindo que a cafeína causa sensibilização aos efeitos locomotores desse derivado anfetamínico.Caffeine and femproporex are psychostimulants drugs widely consumed in Brazil. Behavioral sensitization is defined as an augmentation in the behavioral effect of a psychostimulant upon re-administration. Repeated administration of a psychostimulant produces behavioral sensitization to that drug and cross-sensitization to other drugs. We investigated whether repeated administration of caffeine increases femproporex-induced locomotor activity in adolescent and adult rats. Forty-eight adolescent (postnatal day 27 and 32 adult

  11. Helminth induced suppression of macrophage activation is correlated with inhibition of calcium channel activity.

    Directory of Open Access Journals (Sweden)

    Arun Chauhan

    Full Text Available Helminth parasites cause persistent infections in humans and yet many infected individuals are asymptomatic. Neurocysticercosis (NCC, a disease of the central nervous system (CNS caused by the cestode Taenia solium, has a long asymptomatic phase correlated with an absence of brain inflammation. However, the mechanisms of immune suppression remain poorly understood. Here we report that murine NCC displays a lack of cell surface maturation markers in infiltrating myeloid cells. Furthermore, soluble parasite ligands (PL failed to induce maturation of macrophages, and inhibited TLR-induced inflammatory cytokine production. Importantly, PL treatment abolished both LPS and thapsigargin-induced store operated Ca2+ entry (SOCE. Moreover, electrophysiological recordings demonstrated PL-mediated inhibition of LPS or Tg-induced currents that were TRPC1-dependent. Concomitantly STIM1-TRPC1 complex was also impaired that was essential for SOCE and sustained Ca2+ entry. Likewise loss of SOCE due to PL further inhibited NFkB activation. Overall, our results indicate that the negative regulation of agonist induced Ca2+ signaling pathway by parasite ligands may be a novel immune suppressive mechanism to block the initiation of the inflammatory response associated with helminth infections.

  12. The interpretation of mu suppression as an index of mirror neuron activity: past, present and future

    Science.gov (United States)

    2017-01-01

    Mu suppression studies have been widely used to infer the activity of the human mirror neuron system (MNS) in a number of processes, ranging from action understanding, language, empathy and the development of autism spectrum disorders (ASDs). Although mu suppression is enjoying a resurgence of interest, it has a long history. This review aimed to revisit mu's past, and examine its recent use to investigate MNS involvement in language, social processes and ASDs. Mu suppression studies have largely failed to produce robust evidence for the role of the MNS in these domains. Several key potential shortcomings with the use and interpretation of mu suppression, documented in the older literature and highlighted by more recent reports, are explored here. PMID:28405354

  13. Osteoclast activated FoxP3+ CD8+ T-cells suppress bone resorption in vitro.

    Directory of Open Access Journals (Sweden)

    Zachary S Buchwald

    Full Text Available BACKGROUND: Osteoclasts are the body's sole bone resorbing cells. Cytokines produced by pro-inflammatory effector T-cells (T(EFF increase bone resorption by osteoclasts. Prolonged exposure to the T(EFF produced cytokines leads to bone erosion diseases such as osteoporosis and rheumatoid arthritis. The crosstalk between T-cells and osteoclasts has been termed osteoimmunology. We have previously shown that under non-inflammatory conditions, murine osteoclasts can recruit naïve CD8 T-cells and activate these T-cells to induce CD25 and FoxP3 (Tc(REG. The activation of CD8 T-cells by osteoclasts also induced the cytokines IL-2, IL-6, IL-10 and IFN-γ. Individually, these cytokines can activate or suppress osteoclast resorption. PRINCIPAL FINDINGS: To determine the net effect of Tc(REG on osteoclast activity we used a number of in vitro assays. We found that Tc(REG can potently and directly suppress bone resorption by osteoclasts. Tc(REG could suppress osteoclast differentiation and resorption by mature osteoclasts, but did not affect their survival. Additionally, we showed that Tc(REG suppress cytoskeletal reorganization in mature osteoclasts. Whereas induction of Tc(REG by osteoclasts is antigen-dependent, suppression of osteoclasts by Tc(REG does not require antigen or re-stimulation. We demonstrated that antibody blockade of IL-6, IL-10 or IFN-γ relieved suppression. The suppression did not require direct contact between the Tc(REG and osteoclasts. SIGNIFICANCE: We have determined that osteoclast-induced Tc(REG can suppress osteoclast activity, forming a negative feedback system. As the CD8 T-cells are activated in the absence of inflammatory signals, these observations suggest that this regulatory loop may play a role in regulating skeletal homeostasis. Our results provide the first documentation of suppression of osteoclast activity by CD8 regulatory T-cells and thus, extend the purview of osteoimmunology.

  14. Emergence of spatially heterogeneous burst suppression in a neural field model of electrocortical activity

    Directory of Open Access Journals (Sweden)

    Ingo eBojak

    2015-02-01

    Full Text Available Burst suppression in the electroencephalogram (EEG is a well described phenomenon that occurs during deep anaesthesia, as well as in a variety of congenital and acquired brain insults. Classically it is thought of as spatially synchronous, quasi-periodic bursts of high amplitude EEG separated by low amplitude activity. However, its characterisation as a ``global brain state'' has been challenged by recent results obtained with intracranial electrocortigraphy. Not only does it appear that burst suppression activity is highly asynchronous across cortex, but also that it may occur in isolated regions of circumscribed spatial extent. Here we outline a realistic neural field model for burst suppression by adding a slow process of synaptic resource depletion and recovery, which is able to reproduce qualitatively the empirically observed features during general anaesthesia at the whole cortex level. Simulations reveal heterogeneous bursting over the model cortex and complex spatiotemporal dynamics during simulated anaesthetic action, and provide forward predictions of neuroimaging signals for subsequent empirical comparisons and more detailed characterisation.Because burst suppression corresponds to a dynamical end-point of brain activity, theoretically accounting for its spatiotemporal emergence will vitally contribute to efforts aimed at clarifying whether a common physiological trajectory is induced by the actions of general anaesthetic agents. We have taken a first step in this direction by showing that a neural field model can qualitatively match recent experimental data that indicate spatial differentiation of burst suppression activity across cortex.

  15. Polyphenol derivatives inhibit human neutrophil activity by suppressing oxidative burst

    Czech Academy of Sciences Publication Activity Database

    Drábiková, K.; Perečko, T.; Nosáľ, R.; Harmatha, Juraj; Šmidrkal, J.; Jančinová, V.

    2012-01-01

    Roč. 5, Suppl.1 (2012), s. 31-31 ISSN 1337-6853. [Interdisciplinary Toxicological Conference & Advanced Toxicological Course /17./. 27.08.2012-31.08.2012, Stará Lesná] Institutional research plan: CEZ:AV0Z40550506 Keywords : polyphenol derivatives * neutrophil activity * pinosylvin Subject RIV: CC - Organic Chemistry

  16. Active power filter equivalent to an infinite feeder for harmonic suppression in radial distribution systems

    DEFF Research Database (Denmark)

    Shen, Hong; Yang, Lili; Sun, Xiaofeng

    2016-01-01

    This study proposes to install a novel active power filter (IF-APF) mimicking the character of an infinitely long transmission line at the end of a radial feeder. The proposed IF-APF eliminates the reflected wave and realises the background harmonic voltage suppression capability throughout...... the feeder by mimicking the characteristic of an infinite feeder. The proposed IF-APF shows a better harmonic damping performance than the traditional resistive active power filter (R-APF). Moreover, the proposed IF-APF achieves a better harmonic suppression performance than the traditional R-APF, especially...

  17. Dopa therapy and action impulsivity: subthreshold error activation and suppression in Parkinson's disease.

    Science.gov (United States)

    Fluchère, Frédérique; Deveaux, Manon; Burle, Borís; Vidal, Franck; van den Wildenberg, Wery P M; Witjas, Tatiana; Eusebio, Alexandre; Azulay, Jean-Philippe; Hasbroucq, Thierry

    2015-05-01

    Impulsive actions entail (1) capture of the motor system by an action impulse, which is an urge to act and (2) failed suppression of that impulse in order to prevent a response error. Several studies indicate that dopaminergic treatment can induce action impulsivity in patients diagnosed with Parkinson's disease (PD). Whether this effect is due to increased impulse expression or to decreased impulse suppression remains to be deciphered. We used a novel approach based on electromyographic (EMG) analyses to decipher the effects of the patient's usual dopaminergic therapy on the expression and suppression of subliminal erroneous impulses. To this end, we used a within-subject design and took advantage of the Simon task, that elicits prepotent response tendencies. The patients (N = 15) performed the task on their usual dopaminergic medication and after complete medication withdrawal (for at least 12 h). The correction rate that measures the ability to suppress subthreshold impulsive muscle activity was lower when the patients were on medication as compared to their off medication state (p < 0.05). The incorrect activation rate that measures the capture of the motor system by action impulses was unaffected by medication. Dopa therapy affected action impulsivity. Although medication did not influence the incidence of fast action impulses, it significantly reduced patients' ability to abort and suppress muscle activation related to the incorrect response alternative.

  18. Suppression of leukocyte inhibitory factor (LIF) production and [3H]thymidine incorporation by concanavalin A-activated mononuclear cells

    International Nuclear Information System (INIS)

    Lomnitzer, R.; Rabson, A.R.

    1979-01-01

    The capacity of human mononuclear (MN) cells pretreated with concanavalin A (Con A) to suppress the activity of fresh phytohemagglutinin (PHA)-pulsed mononuclear cells was assessed. Con A-pretreated MN cells suppressed leukocyte inhibitory factor (LIF) activity in supernatants of PHA-pulsed cell cultures and [ 3 H]thymidine incorporation by these cells. Suppression was obtained in both allogeneic and autologous systems with mitomycin-treated, irradiated, or untreated Con A-induced cells. Lymphocytes from two patients that, following treatment with Con A, did not suppress mitogen-induced proliferative response of normal cells also did not suppress LIF production

  19. Oral activated charcoal suppresses hyperphosphataemia in haemodialysis patients.

    Science.gov (United States)

    Wang, Zunsong; Cui, Meiyu; Tang, Lijun; Li, Wenbin; Wei, Yong; Zhu, Zhuxian; Jia, Xiaoyan; Kong, Xianglei; Xu, Dongmei

    2012-09-01

    Hyperphosphataemia is almost inevitable in end stage renal disease (ESRD) patients and is associated with increased morbidity and mortality. In this study we examined whether oral activated charcoal (oAC) reduces serum phosphate level in haemodialysis patients. This was an open-label, prospective, uncontrolled study. One hundred and thirty-five haemodialysis patients were included in this study, with cessation of treatment with any phosphate binders during a 2 week washout period. Patients with serum phosphate levels greater than 5.5 mg/dL during the washout period were included for treatment with oAC. oAC was started at a dose of 600 mg three times per day with meals and was administered for 24 weeks. oAC dose was titrated up during the 24 week period to achieve phosphate control (3.5-5.5 mg/dL). A second 2 week washout period followed the end of oAC treatment. In the 114 patients who successfully completed the trial, the mean dose of activated charcoal was 3190 ± 806 mg/day. oAC reduced mean phosphate levels to below 5.5 mg/dL, with mean decreases of 2.60 ± 0.11 mg/dL (P < 0.01) and 103 (90.4%) of the patients reached the phosphate target. After the second washout period the phosphate levels increased to 7.50 ± 1.03 mg/dL (P < 0.01). Serum intact parathyroid hormone (iPTH) levels declined from 338.75 ± 147.77 pg/mL to 276.51 ± 127.82 pg/mL (P < 0.05) during the study. oAC had no influence on serum prealbumin, total cholesterol, triglycerides, serum ferritin, haemoglobin or platelet levels and the levels of 1,25-dihydroxyvitamin D were stable during the study. In this open-label uncontrolled study, oAC effectively controls hyperphosphataemia and hyperparathyroidism in haemodialysis patients. The safety and efficacy of oAC needs to be assessed in a randomized controlled trial. © 2012 The Authors. Nephrology © 2012 Asian Pacific Society of Nephrology.

  20. The ventromedial hypothalamus oxytocin induces locomotor behavior regulated by estrogen.

    Science.gov (United States)

    Narita, Kazumi; Murata, Takuya; Matsuoka, Satoshi

    2016-10-01

    Our previous studies demonstrated that excitation of neurons in the rat ventromedial hypothalamus (VMH) induced locomotor activity. An oxytocin receptor (Oxtr) exists in the VMH and plays a role in regulating sexual behavior. However, the role of Oxtr in the VMH in locomotor activity is not clear. In this study we examined the roles of oxytocin in the VMH in running behavior, and also investigated the involvement of estrogen in this behavioral change. Microinjection of oxytocin into the VMH induced a dose-dependent increase in the running behavior in male rats. The oxytocin-induced running activity was inhibited by simultaneous injection of Oxtr-antagonist, (d(CH2)5(1), Try(Me)(2), Orn(8))-oxytocin. Oxytocin injection also induced running behavior in ovariectomized (OVX) female rats. Pretreatment of the OVX rats with estrogen augmented the oxytocin-induced running activity twofold, and increased the Oxtr mRNA in the VMH threefold. During the estrus cycle locomotor activity spontaneously increased in the dark period of proestrus. The Oxtr mRNA was up-regulated in the proestrus afternoon. Blockade of oxytocin neurotransmission by its antagonist before the onset of the dark period of proestrus decreased the following nocturnal locomotor activity. These findings demonstrate that Oxtr in the VMH is involved in the induction of running behavior and that estrogen facilitates this effect by means of Oxtr up-regulation, suggesting the involvement of oxytocin in the locomotor activity of proestrus female rats. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. The effects of noradrenaline on locomotor rhythm generating networks in the isolated neonatal rat spinal cord

    DEFF Research Database (Denmark)

    Kiehn, Ole; Sillar, Keith T.; Kjaerulff, O.

    1999-01-01

    activity of the ongoing rhythm. Moreover, NA did not obviously affect the left/right and rostrocaudal alternation of the NMDA/5-HT rhythm. The NMDA/5-HT locomotor rhythm sometimes displayed a time-dependent breakdown in coordination, ultimately resulting in tonic ventral root activity. However......, the addition of NA to the NMDA/5-HT saline could reinstate a well-coordinated locomotor rhythm. We conclude that exogenously applied NA can elicit tonic activity or can trigger a slow, irregular and often synchronous motor pattern. When NA is applied during ongoing locomotor activity, the amine has a distinct...

  2. LFP Oscillations in the Mesencephalic Locomotor Region during Voluntary Locomotion

    Directory of Open Access Journals (Sweden)

    Brian R. Noga

    2017-05-01

    Full Text Available Oscillatory rhythms in local field potentials (LFPs are thought to coherently bind cooperating neuronal ensembles to produce behaviors, including locomotion. LFPs recorded from sites that trigger locomotion have been used as a basis for identification of appropriate targets for deep brain stimulation (DBS to enhance locomotor recovery in patients with gait disorders. Theta band activity (6–12 Hz is associated with locomotor activity in locomotion-inducing sites in the hypothalamus and in the hippocampus, but the LFPs that occur in the functionally defined mesencephalic locomotor region (MLR during locomotion have not been determined. Here we record the oscillatory activity during treadmill locomotion in MLR sites effective for inducing locomotion with electrical stimulation in rats. The results show the presence of oscillatory theta rhythms in the LFPs recorded from the most effective MLR stimulus sites (at threshold ≤60 μA. Theta activity increased at the onset of locomotion, and its power was correlated with the speed of locomotion. In animals with higher thresholds (>60 μA, the correlation between locomotor speed and theta LFP oscillations was less robust. Changes in the gamma band (previously recorded in vitro in the pedunculopontine nucleus (PPN, thought to be a part of the MLR were relatively small. Controlled locomotion was best achieved at 10–20 Hz frequencies of MLR stimulation. Our results indicate that theta and not delta or gamma band oscillation is a suitable biomarker for identifying the functional MLR sites.

  3. LFP Oscillations in the Mesencephalic Locomotor Region during Voluntary Locomotion.

    Science.gov (United States)

    Noga, Brian R; Sanchez, Francisco J; Villamil, Luz M; O'Toole, Christopher; Kasicki, Stefan; Olszewski, Maciej; Cabaj, Anna M; Majczyński, Henryk; Sławińska, Urszula; Jordan, Larry M

    2017-01-01

    Oscillatory rhythms in local field potentials (LFPs) are thought to coherently bind cooperating neuronal ensembles to produce behaviors, including locomotion. LFPs recorded from sites that trigger locomotion have been used as a basis for identification of appropriate targets for deep brain stimulation (DBS) to enhance locomotor recovery in patients with gait disorders. Theta band activity (6-12 Hz) is associated with locomotor activity in locomotion-inducing sites in the hypothalamus and in the hippocampus, but the LFPs that occur in the functionally defined mesencephalic locomotor region (MLR) during locomotion have not been determined. Here we record the oscillatory activity during treadmill locomotion in MLR sites effective for inducing locomotion with electrical stimulation in rats. The results show the presence of oscillatory theta rhythms in the LFPs recorded from the most effective MLR stimulus sites (at threshold ≤60 μA). Theta activity increased at the onset of locomotion, and its power was correlated with the speed of locomotion. In animals with higher thresholds (>60 μA), the correlation between locomotor speed and theta LFP oscillations was less robust. Changes in the gamma band (previously recorded in vitro in the pedunculopontine nucleus (PPN), thought to be a part of the MLR) were relatively small. Controlled locomotion was best achieved at 10-20 Hz frequencies of MLR stimulation. Our results indicate that theta and not delta or gamma band oscillation is a suitable biomarker for identifying the functional MLR sites.

  4. Serotonin (5-HT) precursor loading with 5-hydroxy-l-tryptophan (5-HTP) reduces locomotor activation produced by (+)-amphetamine in the rat.

    Science.gov (United States)

    Baumann, Michael H; Williams, Zakia; Zolkowska, Dorota; Rothman, Richard B

    2011-04-01

    Evidence suggests that increases in synaptic serotonin (5-HT) can reduce the stimulant properties of amphetamine-type drugs. Here we tested the hypothesis that administration of the 5-HT precursor 5-hydroxy-l-tryptophan (5-HTP), along with the peripheral decarboxylase inhibitor benserazide, would decrease locomotor effects of (+)-amphetamine. Drug treatments were administered to conscious male rats undergoing in vivo microdialysis in nucleus accumbens. During dialysis sampling, rats were housed in chambers equipped with photobeams to detect forward locomotion (i.e., ambulation) and repetitive movements (i.e., stereotypy). Extracellular concentrations of dopamine (DA) and 5-HT were measured by high-pressure liquid chromatography with electrochemical detection. 5-HTP (10 & 30 mg/kg, i.p.) plus benserazide (30 mg/kg, i.p.) caused dose-related increases in 5-HT but failed to alter other parameters. (+)-Amphetamine (0.3 & 1.0 mg/kg, i.p.) produced dose-related increases in DA, ambulation and stereotypy. Combined administration of 5-HTP and (+)-amphetamine evoked large elevations in extracellular DA and 5-HT, but caused significantly less ambulation than (+)-amphetamine alone (~50% reduction). Our results confirm that 5-HTP can decrease hyperactivity produced by (+)-amphetamine, even in the presence of elevations in dialysate DA. The data suggest that 5-HTP and (+)-amphetamine may be useful to broadly enhance monoamine function in the clinical setting, while reducing undesirable effects of (+)-amphetamine. Published by Elsevier Ireland Ltd.

  5. Salidroside Suppresses HUVECs Cell Injury Induced by Oxidative Stress through Activating the Nrf2 Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Yao Zhu

    2016-08-01

    Full Text Available Oxidative stress plays an important role in the pathogenesis of cardiovascular diseases. Salidroside (SAL, one of the main effective constituents of Rhodiola rosea, has been reported to suppress oxidative stress-induced cardiomyocyte injury and necrosis by promoting transcription of nuclear factor E2-related factor 2 (Nrf2-regulated genes such as heme oxygenase-1 (HO-1 and NAD(PH dehydrogenase (quinone1 (NQO1. However, it has not been indicated whether SAL might ameliorate endothelial injury induced by oxidative stress. Here, our study demonstrated that SAL might suppress HUVEC cell injury induced by oxidative stress through activating the Nrf2 signaling pathway. The results of our study indicated that SAL decreased the levels of intercellular reactive oxygen species (ROS and malondialdehyde (MDA, and improved the activities of superoxide dismutase (SOD and catalase (CAT, resulting in protective effects against oxidative stress-induced cell damage in HUVECs. It suppressed oxidative stress damage by inducing Nrf2 nuclear translocation and activating the expression of Nrf2-regulated antioxidant enzyme genes such as HO-1 and NQO1 in HUVECs. Knockdown of Nrf2 with siRNA abolished the cytoprotective effects against oxidative stress, decreased the expression of Nrf2, HO-1, and NQO1, and inhibited the nucleus translocation of Nrf2 in HUVECs. This study is the first to demonstrate that SAL suppresses HUVECs cell injury induced by oxidative stress through activating the Nrf2 signaling pathway.

  6. Developing the content of a locomotor disability scale for adults in Bangladesh: a qualitative study.

    Science.gov (United States)

    Mahmud, Ilias; Clarke, Lynda; Ploubidis, George B

    2017-01-01

    Bangladesh has an estimated 17 million adults with disabilities. A significant proportion of them are believed to have locomotor disabilities. There are over 300 non-governmental organizations providing different types of rehabilitation services to them. However, there is no locally developed and validated locomotor disability measurement scale in Bangladesh. The purpose of this study was to develop a locomotor disability scale with disability indicators suitable for adults in Bangladesh. Semi-structured interviews were conducted with 25 purposively selected adults with locomotor disabilities to generate scale items. At the second stage, cognitive interviews were conducted with 12 purposively selected adults with locomotor disabilities in order to refine the measurement questions and response categories. Data were analysed using the framework technique- identifying, abstracting, charting and matching themes across the interviews. For a locomotor disability scale, 70 activities (disability indicators) were identified: 37 mobility activities, 9 activities of daily living, 17 work/productivity activities and 7 leisure activities. Cognitive interviews revealed that when asking the respondents to rate their difficulty in performing the activities, instead of just mentioning the activity name, such as taking a bath or shower, a detailed description of the activity and response options were necessary to ensure consistent interpretation of the disability indicators and response options across all respondents. Identifying suitable disability indicators was the first step in developing a locomotor disability scale for adults in Bangladesh. Interviewing adults with locomotor disabilities in Bangladesh ensured that the locomotor disability scale is of relevance to them and consequently it has excellent content validity. Further research is needed to evaluate the psychometric properties of this scale.

  7. Cyclin F suppresses B-Myb activity to promote cell cycle checkpoint control

    DEFF Research Database (Denmark)

    Klein, Ditte Kjærsgaard; Hoffmann, Saskia; Ahlskog, Johanna K

    2015-01-01

    an important role in checkpoint control following ionizing radiation. Cyclin F-depleted cells initiate checkpoint signalling after ionizing radiation, but fail to maintain G2 phase arrest and progress into mitosis prematurely. Importantly, cyclin F suppresses the B-Myb-driven transcriptional programme...... that promotes accumulation of crucial mitosis-promoting proteins. Cyclin F interacts with B-Myb via the cyclin box domain. This interaction is important to suppress cyclin A-mediated phosphorylation of B-Myb, a key step in B-Myb activation. In summary, we uncover a regulatory mechanism linking the F-box protein...

  8. Serotonin suppresses food anticipatory activity and synchronizes the food-entrainable oscillator during time-restricted feeding.

    Science.gov (United States)

    Rozenblit-Susan, Sigal; Chapnik, Nava; Genzer, Yoni; Froy, Oren

    2016-01-15

    The serotonergic and circadian systems are intertwined as serotonin modulates the response of the central brain suprachiasmatic nuclei (SCN) clock to light. Time-restricted feeding (RF) is characterized by increased food anticipatory activity (FAA) and controlled by the food-entrainable oscillator (FEO) rather than the SCN. Our objective was to test whether serotonin affects the FEO. Mice were treated with the selective serotonin reuptake inhibitor (SSRI) fluvoxamine (FLX) or the tryptophan hydroxylase inhibitor parachlorophenylalanine (PCPA) and locomotor activity under ad libitum feeding, RF and different lighting conditions was monitored. Under AL, FLX administration did not affect 24-h locomotor activity, while mice treated with PCPA exhibited increased activity. RF-FLX-treated mice showed less FAA 2h before food availability (ZT2-ZT4) compared to RF- or RF-PCPA-fed mice. Under DD, RF-PCPA-treated mice displayed increased activity, as was seen under LD conditions. Surprisingly, RF-PCPA-treated mice showed free running in the FAA component. These results emphasize the role of serotonin in SCN-mediated activity inhibition and FEO entrainment and activity. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. Deletion of mammalian sterile 20-like kinase 1 attenuates neuronal loss and improves locomotor function in a mouse model of spinal cord trauma.

    Science.gov (United States)

    Wang, Pan-Feng; Xu, Da-Yuan; Zhang, Yuntong; Liu, Xiao-Bin; Xia, Yan; Zhou, Pan-Yu; Fu, Qing-Ge; Xu, Shuo-Gui

    2017-07-01

    Neuronal cell death following spinal cord injury (SCI) is an important contributor to neurological deficits. The purpose of our work was to delineate the function of mammalian sterile 20-like kinase 1 (Mst1), a pro-apoptotic kinase and key mediator of apoptotic signaling, in the pathogenesis of an experimental mouse model of SCI. Male mice received a mid-thoracic spinal contusion injury, and it was found that phosphorylation of Mst1 at the injured site was enhanced significantly following SCI. Furthermore, when compared to the wild-type controls, Mst1-deficient mice displayed improved locomotor function by increased Basso mouse scale score. Deletion of Mst1 in mice attenuated loss of motor neurons and suppressed microglial and glial activation following SCI. Deletion of Mst1 in mice reduced apoptosis via suppressing cytochrome c release and caspase-3 activation following SCI. Deletion of Mst1 attenuated mitochondrial dysfunction and increased ATP formation following SCI. Deletion of Mst1 in mice inhibited local inflammation following SCI, evidenced by reduced activities of myeloperoxidase and protein levels of TNF-α, IL-1β, and IL-6. In conclusion, the present study demonstrated that deletion of Mst1 attenuated neuronal loss and improved locomotor function in a mouse model of SCI, via preserving mitochondrial function, attenuating mitochondria-mediated apoptotic pathway, and suppressing inflammation, at least in part.

  10. Suppression of SOS-inducing activity of chemical mutagens by metabolites from microbial transformation of (-)-isolongifolene.

    Science.gov (United States)

    Sakata, Kazuki; Oda, Yoshimitsu; Miyazawa, Mitsuo

    2010-02-24

    In this study, biotransformation of (-)-isolongifolene (1) by Glomerella cingulata and suppressive effect on umuC gene expression by chemical mutagens 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide (furylfuramide) and aflatoxin B(1) (AFB(1)) of the SOS response in Salmonella typhimurium TA1535/pSK1002 were investigated. Initially, 1 was carried out the microbial transformation by G. cingulata. The result found that 1 was converted into (-)-isolongifolen-9-one (2), (-)-(2S)-13-hydroxy-isolongifolen-9-one (3), and (-)-(4R)-4-hydroxy-isolongifolen-9-one (4) by G. cingulata, and their conversion rates were 60, 25, and 15%, respectively. The metabolites suppressed the SOS-inducing activity of furylfuramid and AFB(1) in the umu test. Comound 2 showed gene expression by chemical mutagens furylfuramide and AFB(1) was suppressed 54 and 50% at <0.5 mM, respectively. Compound 2 is the most effective compound in this experiment.

  11. MicroRNA-214 suppresses gluconeogenesis by targeting activating transcriptional factor 4.

    Science.gov (United States)

    Li, Kai; Zhang, Jin; Yu, Junjie; Liu, Bin; Guo, Yajie; Deng, Jiali; Chen, Shanghai; Wang, Chunxia; Guo, Feifan

    2015-03-27

    Although the gluconeogenesis pathway is already a target for the treatment of type 2 diabetes, the potential role of microRNAs (miRNAs) in gluconeogenesis remains unclear. Here, we investigated the physiological functions of miR-214 in gluconeogenesis. The expression of miR-214 was suppressed by glucagon via protein kinase A signaling in primary hepatocytes, and miR-214 was down-regulated in the livers of fasted, high fat diet-induced diabetic and leptin receptor-mutated (db/db) mice. The overexpression of miR-214 in primary hepatocytes suppressed glucose production, and silencing miR-214 reversed this effect. Gluconeogenesis was suppressed in the livers of mice injected with an adenovirus expressing miR-214 (Ad-miR-214). Additionally, Ad-miR-214 alleviated high fat diet-induced elevation of gluconeogenesis and hyperglycemia. Furthermore, we found that activating transcription factor 4 (ATF4), a reported target of miR-214, can reverse the suppressive effect of miR-214 on gluconeogenesis in primary hepatocytes, and this suppressive effect was blocked in liver-specific ATF4 knock-out mice. ATF4 regulated gluconeogenesis via affecting forkhead box protein O1 (FOXO1) transcriptional activity. Finally, liver-specific miR-214 transgenic mice exhibited suppressed gluconeogenesis and reduced expression of ATF4, phosphoenolpyruvate carboxykinase, and glucose-6-phosphatase in liver. Taken together, our results suggest that the miR-214-ATF4 axis is a novel pathway for the regulation of hepatic gluconeogenesis. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  12. MicroRNA-214 Suppresses Gluconeogenesis by Targeting Activating Transcriptional Factor 4*

    Science.gov (United States)

    Li, Kai; Zhang, Jin; Yu, Junjie; Liu, Bin; Guo, Yajie; Deng, Jiali; Chen, Shanghai; Wang, Chunxia; Guo, Feifan

    2015-01-01

    Although the gluconeogenesis pathway is already a target for the treatment of type 2 diabetes, the potential role of microRNAs (miRNAs) in gluconeogenesis remains unclear. Here, we investigated the physiological functions of miR-214 in gluconeogenesis. The expression of miR-214 was suppressed by glucagon via protein kinase A signaling in primary hepatocytes, and miR-214 was down-regulated in the livers of fasted, high fat diet-induced diabetic and leptin receptor-mutated (db/db) mice. The overexpression of miR-214 in primary hepatocytes suppressed glucose production, and silencing miR-214 reversed this effect. Gluconeogenesis was suppressed in the livers of mice injected with an adenovirus expressing miR-214 (Ad-miR-214). Additionally, Ad-miR-214 alleviated high fat diet-induced elevation of gluconeogenesis and hyperglycemia. Furthermore, we found that activating transcription factor 4 (ATF4), a reported target of miR-214, can reverse the suppressive effect of miR-214 on gluconeogenesis in primary hepatocytes, and this suppressive effect was blocked in liver-specific ATF4 knock-out mice. ATF4 regulated gluconeogenesis via affecting forkhead box protein O1 (FOXO1) transcriptional activity. Finally, liver-specific miR-214 transgenic mice exhibited suppressed gluconeogenesis and reduced expression of ATF4, phosphoenolpyruvate carboxykinase, and glucose-6-phosphatase in liver. Taken together, our results suggest that the miR-214-ATF4 axis is a novel pathway for the regulation of hepatic gluconeogenesis. PMID:25657009

  13. Locomotor sensitization to ethanol: Contribution of b-Endorphin

    Directory of Open Access Journals (Sweden)

    Stephani eDempsey

    2012-08-01

    Full Text Available Alcohol use disorders, like all drug addictions, involve a constellation of adaptive changes throughout the brain. Neural activity underlying changes in the rewarding properties of alcohol reflect changes in dopamine transmission in mesolimbic and nigrostriatal pathways and these effects are modulated by endogenous opioids such as b-Endorphin. In order to study the role of b-Endorphin in the development of locomotor sensitization to repeated EtOH exposure, we tested transgenic mice that vary in their capacity to synthesize this peptide as a result of constitutive modification of the Pomc gene. Our results indicate that mice deficient in b-Endorphin show attenuated locomotor activation following an acute injection of EtOH (2 g/kg and, in contrast to wildtype mice, fail to demonstrate locomotor sensitization after 12 days of repeated EtOH injections. These data support the idea that b-Endorphin modulates the locomotor effects of EtOH and contributes to the neuroadaptive changes associated with chronic use.

  14. Suppression of superoxide anion generation catalyzed by xanthine oxidase with alkyl caffeates and the scavenging activity.

    Science.gov (United States)

    Masuoka, Noriyoshi; Kubo, Isao

    2016-01-01

    Alkyl caffeates are strong antioxidants and inhibitors of xanthine oxidase. However, it is unclear about the effect of caffeic acid and alkyl caffeates on superoxide anion (O2(-)) generation catalyzed by xanthine oxidase. Effects of caffeic acid and alkyl caffeates on the uric acid formation and O2(-) generation catalyzed by xanthine oxidase were analyzed. The scavenging activities of 1,1-diphenyl-2-picryhydrazyl (DPPH) radical and O2(-) generated with phenazine methosulfate (PMS) and NADH were examined. Caffeic acid derivatives equally suppressed O2(-) generation, and the suppression is stronger than inhibition of xanthine oxidase. Scavenging activity of O2(-) is low compared to the suppression of O2(-) generation. Suppression of O2(-) generation catalyzed by xanthine oxidase with caffeic acid derivatives was not due to enzyme inhibition or O2(-) scavenging but due to the reduction of xanthine oxidase molecules. Alkyl caffeates are effective inhibitors of uric acid and O2(-) catalyzed by xanthine oxidase as well as antioxidants for edible oil.

  15. Effects of carotenoids, immune activation and immune suppression on the intensity of chronic coccidiosis in greenfinches.

    Science.gov (United States)

    Sepp, Tuul; Karu, Ulvi; Sild, Elin; Männiste, Marju; Hõrak, Peeter

    2011-03-01

    Allocation trade-offs of carotenoids between their use in the immune system and production of integumentary colouration have been suggested as a proximate mechanism maintaining honesty of signal traits. We tested how dietary carotenoid supplementation, immune activation and immune suppression affect intensity of coccidian infection in captive greenfinches Carduelis chloris, a passerine with carotenoid-based plumage. Immune activation with phytohaemagglutinin (PHA) decreased body mass among birds not supplemented with lutein, while among the carotenoid-fed birds, PHA had no effect on mass dynamics. Immune suppression with dexamethasone (DEX) induced loss of body mass and reduced the swelling response to PHA. DEX and PHA increased the concentration of circulating heterophils. Lutein supplementation increased plasma carotenoid levels but had no effect on the swelling response induced by PHA. PHA and DEX treatments did not affect plasma carotenoids. Immune stimulation by PHA suppressed the infection, but only among carotenoid-supplemented birds. Priming of the immune system can thus aid in suppressing chronic infection but only when sufficient amount of carotenoids is available. Our experiment shows the importance of carotenoids in immune response, but also the complicated nature of this impact, which could be the reason for inconsistent results in studies investigating the immunomodulatory effects of carotenoids. The findings about involvement of carotenoids in modulation of an immune response against coccidiosis suggest that carotenoid-based ornaments may honestly signal individuals' ability to manage chronic infections. Copyright © 2010 Elsevier Inc. All rights reserved.

  16. The serotonin reuptake inhibitor citalopram suppresses activity in the neonatal rat barrel cortex in vivo.

    Science.gov (United States)

    Akhmetshina, Dinara; Zakharov, Andrei; Vinokurova, Daria; Nasretdinov, Azat; Valeeva, Guzel; Khazipov, Roustem

    2016-06-01

    Inhibition of serotonin uptake, which causes an increase in extracellular serotonin levels, disrupts the development of thalamocortical barrel maps in neonatal rodents. Previous in vitro studies have suggested that the disruptive effect of excessive serotonin on barrel map formation involves a depression at thalamocortical synapses. However, the effects of serotonin uptake inhibitors on the early thalamocortical activity patterns in the developing barrel cortex in vivo remain largely unknown. Here, using extracellular recordings of the local field potentials and multiple unit activity (MUA) we explored the effects of the selective serotonin reuptake inhibitor (SSRI) citalopram (10-20mg/kg, intraperitoneally) on sensory evoked activity in the barrel cortex of neonatal (postnatal days P2-5) rats in vivo. We show that administration of citalopram suppresses the amplitude and prolongs the delay of the sensory evoked potentials, reduces the power and frequency of the early gamma oscillations, and suppresses sensory evoked and spontaneous neuronal firing. In the adolescent P21-29 animals, citalopram affected neither sensory evoked nor spontaneous activity in barrel cortex. We suggest that suppression of the early thalamocortical activity patterns contributes to the disruption of the barrel map development caused by SSRIs and other conditions elevating extracellular serotonin levels. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Omega-3 free fatty acids suppress macrophage inflammasome activation by inhibiting NF-κB activation and enhancing autophagy.

    Directory of Open Access Journals (Sweden)

    Yolanda Williams-Bey

    Full Text Available The omega-3 (ω3 fatty acid docosahexaenoic acid (DHA can suppress inflammation, specifically IL-1β production through poorly understood molecular mechanisms. Here, we show that DHA reduces macrophage IL-1β production by limiting inflammasome activation. Exposure to DHA reduced IL-1β production by ligands that stimulate the NLRP3, AIM2, and NAIP5/NLRC4 inflammasomes. The inhibition required Free Fatty Acid Receptor (FFAR 4 (also known as GPR120, a G-protein coupled receptor (GPR known to bind DHA. The exposure of cells to DHA recruited the adapter protein β-arrestin1/2 to FFAR4, but not to a related lipid receptor. DHA treatment reduced the initial inflammasome priming step by suppressing the nuclear translocation of NF-κB. DHA also reduced IL-1β levels by enhancing autophagy in the cells. As a consequence macrophages derived from mice lacking the essential autophagy protein ATG7 were partially resistant to suppressive effects of DHA. Thus, DHA suppresses inflammasome activation by two distinct mechanisms, inhibiting the initial priming step and by augmenting autophagy, which limits inflammasome activity.

  18. Deep brain stimulation suppresses pallidal low frequency activity in patients with phasic dystonic movements.

    Science.gov (United States)

    Barow, Ewgenia; Neumann, Wolf-Julian; Brücke, Christof; Huebl, Julius; Horn, Andreas; Brown, Peter; Krauss, Joachim K; Schneider, Gerd-Helge; Kühn, Andrea A

    2014-11-01

    Deep brain stimulation of the globus pallidus internus alleviates involuntary movements in patients with dystonia. However, the mechanism is still not entirely understood. One hypothesis is that deep brain stimulation suppresses abnormally enhanced synchronized oscillatory activity within the motor cortico-basal ganglia network. Here, we explore deep brain stimulation-induced modulation of pathological low frequency (4-12 Hz) pallidal activity that has been described in local field potential recordings in patients with dystonia. Therefore, local field potentials were recorded from 16 hemispheres in 12 patients undergoing deep brain stimulation for severe dystonia using a specially designed amplifier allowing simultaneous high frequency stimulation at therapeutic parameter settings and local field potential recordings. For coherence analysis electroencephalographic activity (EEG) over motor areas and electromyographic activity (EMG) from affected neck muscles were recorded before and immediately after cessation of high frequency stimulation. High frequency stimulation led to a significant reduction of mean power in the 4-12 Hz band by 24.8 ± 7.0% in patients with predominantly phasic dystonia. A significant decrease of coherence between cortical EEG and pallidal local field potential activity in the 4-12 Hz range was revealed for the time period of 30 s after switching off high frequency stimulation. Coherence between EMG activity and pallidal activity was mainly found in patients with phasic dystonic movements where it was suppressed after high frequency stimulation. Our findings suggest that high frequency stimulation may suppress pathologically enhanced low frequency activity in patients with phasic dystonia. These dystonic features are the quickest to respond to high frequency stimulation and may thus directly relate to modulation of pathological basal ganglia activity, whereas improvement in tonic features may depend on long-term plastic changes within the

  19. Serotonergic modulation of post-synaptic inhibition and locomotor alternating pattern in the spinal cord

    Directory of Open Access Journals (Sweden)

    Laurent eVinay

    2014-08-01

    Full Text Available The central pattern generators (CPGs for locomotion, located in the lumbar spinal cord, are functional at birth in the rat. Their maturation occurs during the last few days preceding birth, a period during which the first projections from the brainstem start to reach the lumbar enlargement of the spinal cord. Locomotor burst activity in the mature intact spinal cord alternates between flexor and extensor motoneurons through reciprocal inhibition and between left and right sides through commisural inhibitory interneurons. By contrast, all motor bursts are in phase in the fetus. The alternating pattern disappears after neonatal spinal cord transection which suppresses supraspinal influences upon the locomotor networks. This article will review the role of serotonin (5-HT, in particular 5-HT2 receptors, in shaping the alternating pattern. For instance, pharmacological activation of these receptors restores the left-right alternation after injury. Experiments aimed at either reducing the endogenous level of serotonin in the spinal cord or blocking the activation of 5-HT2 receptors.We then describe recent evidence that the action of 5-HT2 receptors is mediated, at least in part, through a modulation of chloride homeostasis. The postsynaptic action of GABA and glycine depends on the intracellular concentration of chloride ions which is regulated by a protein in the plasma membrane, the K+-Cl− cotransporter (KCC2 extruding both K+ and Cl− ions. Absence or reduction of KCC2 expression leads to a depolarizing action of GABA and glycine and a marked reduction in the strength of postsynaptic inhibition. This latter situation is observed early during development and in several pathological conditions, such as after spinal cord injury, thereby causing spasticity and chronic pain. It was recently shown that specific activation of 5-HT2A receptors is able to up-regulate KCC2, restore endogenous inhibition and reduce spasticity.

  20. Troglitazone inhibits endothelial cell proliferation through suppression of casein kinase 2 activity

    International Nuclear Information System (INIS)

    Lee, Kuy-Sook; Park, Jin-Hee; Lee, Seahyoung; Lim, Hyun-Joung; Jang, Yangsoo; Park, Hyun-Young

    2006-01-01

    Troglitazone, an agonist of peroxisome proliferator activated receptorγ (PPARγ), has been reported to inhibit endothelial cell proliferation by suppressing Akt activation. Recently, it has been also proposed that phosphatase and tensin homolog deleted from chromosome 10 (PTEN) plays an important role in such effect of troglitazone. However, the mechanism of how troglitazone regulates PTEN remains to be elucidated. We therefore investigated the effects of troglitazone on casein kinase 2 (CK2), which is known to negatively regulate PTEN activity. Troglitazone significantly inhibited serum-induced proliferation of HUVEC in a concentration dependent manner. Serum-induced Akt and its downstream signaling pathway activation was attenuated by troglitazone (10 μM) pretreatment. The phosphorylation of PTEN, which was directly related to Akt activation, was decreased with troglitazone pretreatment and was inversely proportional to CK2 activity. DRB, a CK2 inhibitor, also showed effects similar to that of troglitazone on Akt and its downstream signaling molecules. In conclusion, our results suggest that troglitazone inhibits proliferation of HUVECs through suppression of CK2 activity rendering PTEN to remain activated, and this effect of troglitazone in HUVECs seems to be PPARγ independent

  1. Sex difference in sensitization to the locomotor effects of mazindol in rats.

    Science.gov (United States)

    Zanin, M; Takahashi, R N

    1994-01-01

    Male and female rats were treated daily for 7 days with mazindol (5, 10, and 20 mg/kg), an anorectic drug, and tested in the open field. Mazindol developed sensitization to its locomotor stimulatory effect in both sexes on day 7 with a nondose-dependent pattern of response. However, the locomotor activity appeared to be sex dependent, female rats being more sensitive. Following a challenge dose of mazindol (10 and 20 mg/kg) on day 10, a marked enhancement of locomotion was seen in female rats. These findings indicate that repeated administration of mazindol produces sex-dependent sensitization to its effect on locomotor behavior.

  2. Apparent suppression of MMP-9 activity by GD1a as determined by gelatin zymography.

    Science.gov (United States)

    Hu, Dan; Tan, Xuan; Sato, Toshinori; Yamagata, Sadako; Yamagata, Tatsuya

    2006-10-13

    Gelatin zymography is widely used to detect and evaluate matrix metalloproteinase-9 (MMP-9) activity. MMP-9 transcription was previously shown to be negatively regulated by ganglioside GD1a [D. Hu, Z. Man, T. Xuan, P. Wang, T. Takaku, S. Hyuga, X.S. Yao, T. Sato, S. Yamagata, T. Yamagata, Ganglioside GD1a regulation of matrix metalloproteinase-9 (MMP-9) expression in mouse FBJ cell Lines: GD1a suppression of MMP-9 expression stimulated by PI3K-Akt and p38 though not by the Erk signaling pathway, 2006, submitted for publication.]. Zymography of MMP-9 of FBJ-M5 cells preincubated with GD1a indicated a greater decrease in activity than expected from mRNA suppression. Incubation of conditioned medium containing MMP-9 with GD1a caused MMP-9 activity to decrease. Examination was thus made to confirm that MMP-9 activity is actually suppressed and/or MMP-9 protein undergoes degradation by GD1a. GD1a was found to have no effect on MMP-9 activity and Western blots indicated GD1a not to diminish MMP-9 during electrophoresis under reducing conditions. GD1a appeared to mediate the binding of a portion of MMP-9 with certain molecules, with consequently greater molecular mass on the gel, to cause decrease in the activity of MMP-9 at the site where it would normally appear. Caution should be used in doing gelatin zymography since molecules other than GD1a may similarly work, causing decrease in MMP-9 activity in zymography.

  3. Resveratrol suppresses IGF-1 induced human colon cancer cell proliferation and elevates apoptosis via suppression of IGF-1R/Wnt and activation of p53 signaling pathways

    Directory of Open Access Journals (Sweden)

    Radhakrishnan Sridhar

    2010-05-01

    Full Text Available Abstract Background Obesity is a global phenomenon and is associated with various types of cancer, including colon cancer. There is a growing interest for safe and effective bioactive compounds that suppress the risk for obesity-promoted colon cancer. Resveratrol (trans-3, 4', 5,-trihydroxystilbene, a stilbenoid found in the skin of red grapes and peanuts suppresses many types of cancers by regulating cell proliferation and apoptosis through a variety of mechanisms, however, resveratrol effects on obesity-promoted colon cancer are not clearly established. Methods We investigated the anti-proliferative effects of resveratrol on HT-29 and SW480 human colon cancer cells in the presence and absence of insulin like growth factor-1 (IGF-1; elevated during obesity and elucidated the mechanisms of action using IGF-1R siRNA in HT-29 cells which represents advanced colon carcinogenesis. Results Resveratrol (100-150 μM exhibited anti-proliferative properties in HT-29 cells even after IGF-1 exposure by arresting G0/G1-S phase cell cycle progression through p27 stimulation and cyclin D1 suppression. Treatment with resveratrol suppressed IGF-1R protein levels and concurrently attenuated the downstream Akt/Wnt signaling pathways that play a critical role in cell proliferation. Targeted suppression of IGF-1R using IGF-1R siRNA also affected these signaling pathways in a similar manner. Resveratrol treatment induced apoptosis by activating tumor suppressor p53 protein, whereas IGF-1R siRNA treatment did not affect apoptosis. Our data suggests that resveratrol not only suppresses cell proliferation by inhibiting IGF-1R and its downstream signaling pathways similar to that of IGF-1R siRNA but also enhances apoptosis via activation of the p53 pathway. Conclusions For the first time, we report that resveratrol suppresses colon cancer cell proliferation and elevates apoptosis even in the presence of IGF-1 via suppression of IGF-1R/Akt/Wnt signaling pathways and

  4. Resveratrol suppresses IGF-1 induced human colon cancer cell proliferation and elevates apoptosis via suppression of IGF-1R/Wnt and activation of p53 signaling pathways

    International Nuclear Information System (INIS)

    Vanamala, Jairam; Reddivari, Lavanya; Radhakrishnan, Sridhar; Tarver, Chris

    2010-01-01

    Obesity is a global phenomenon and is associated with various types of cancer, including colon cancer. There is a growing interest for safe and effective bioactive compounds that suppress the risk for obesity-promoted colon cancer. Resveratrol (trans-3, 4', 5,-trihydroxystilbene), a stilbenoid found in the skin of red grapes and peanuts suppresses many types of cancers by regulating cell proliferation and apoptosis through a variety of mechanisms, however, resveratrol effects on obesity-promoted colon cancer are not clearly established. We investigated the anti-proliferative effects of resveratrol on HT-29 and SW480 human colon cancer cells in the presence and absence of insulin like growth factor-1 (IGF-1; elevated during obesity) and elucidated the mechanisms of action using IGF-1R siRNA in HT-29 cells which represents advanced colon carcinogenesis. Resveratrol (100-150 μM) exhibited anti-proliferative properties in HT-29 cells even after IGF-1 exposure by arresting G 0 /G 1 -S phase cell cycle progression through p27 stimulation and cyclin D1 suppression. Treatment with resveratrol suppressed IGF-1R protein levels and concurrently attenuated the downstream Akt/Wnt signaling pathways that play a critical role in cell proliferation. Targeted suppression of IGF-1R using IGF-1R siRNA also affected these signaling pathways in a similar manner. Resveratrol treatment induced apoptosis by activating tumor suppressor p53 protein, whereas IGF-1R siRNA treatment did not affect apoptosis. Our data suggests that resveratrol not only suppresses cell proliferation by inhibiting IGF-1R and its downstream signaling pathways similar to that of IGF-1R siRNA but also enhances apoptosis via activation of the p53 pathway. For the first time, we report that resveratrol suppresses colon cancer cell proliferation and elevates apoptosis even in the presence of IGF-1 via suppression of IGF-1R/Akt/Wnt signaling pathways and activation of p53, suggesting its potential role as a

  5. Fluctuation-Driven Neural Dynamics Reproduce Drosophila Locomotor Patterns.

    Directory of Open Access Journals (Sweden)

    Andrea Maesani

    2015-11-01

    Full Text Available The neural mechanisms determining the timing of even simple actions, such as when to walk or rest, are largely mysterious. One intriguing, but untested, hypothesis posits a role for ongoing activity fluctuations in neurons of central action selection circuits that drive animal behavior from moment to moment. To examine how fluctuating activity can contribute to action timing, we paired high-resolution measurements of freely walking Drosophila melanogaster with data-driven neural network modeling and dynamical systems analysis. We generated fluctuation-driven network models whose outputs-locomotor bouts-matched those measured from sensory-deprived Drosophila. From these models, we identified those that could also reproduce a second, unrelated dataset: the complex time-course of odor-evoked walking for genetically diverse Drosophila strains. Dynamical models that best reproduced both Drosophila basal and odor-evoked locomotor patterns exhibited specific characteristics. First, ongoing fluctuations were required. In a stochastic resonance-like manner, these fluctuations allowed neural activity to escape stable equilibria and to exceed a threshold for locomotion. Second, odor-induced shifts of equilibria in these models caused a depression in locomotor frequency following olfactory stimulation. Our models predict that activity fluctuations in action selection circuits cause behavioral output to more closely match sensory drive and may therefore enhance navigation in complex sensory environments. Together these data reveal how simple neural dynamics, when coupled with activity fluctuations, can give rise to complex patterns of animal behavior.

  6. Active Vibration Suppression of a 3-DOF Flexible Parallel Manipulator Using Efficient Modal Control

    Directory of Open Access Journals (Sweden)

    Quan Zhang

    2014-01-01

    Full Text Available This paper addresses the dynamic modeling and efficient modal control of a planar parallel manipulator (PPM with three flexible linkages actuated by linear ultrasonic motors (LUSM. To achieve active vibration control, multiple lead zirconate titanate (PZT transducers are mounted on the flexible links as vibration sensors and actuators. Based on Lagrange’s equations, the dynamic model of the flexible links is derived with the dynamics of PZT actuators incorporated. Using the assumed mode method (AMM, the elastic motion of the flexible links are discretized under the assumptions of pinned-free boundary conditions, and the assumed mode shapes are validated through experimental modal test. Efficient modal control (EMC, in which the feedback forces in different modes are determined according to the vibration amplitude or energy of their own, is employed to control the PZT actuators to realize active vibration suppression. Modal filters are developed to extract the modal displacements and velocities from the vibration sensors. Numerical simulation and vibration control experiments are conducted to verify the proposed dynamic model and controller. The results show that the EMC method has the capability of suppressing multimode vibration simultaneously, and both the structural and residual vibrations of the flexible links are effectively suppressed using EMC approach.

  7. TET1 Suppresses Cancer Invasion by Activating the Tissue Inhibitors of Metalloproteinases

    Directory of Open Access Journals (Sweden)

    Chih-Hung Hsu

    2012-09-01

    Full Text Available Tumor suppressor gene silencing through cytosine methylation contributes to cancer formation. Whether DNA demethylation enzymes counteract this oncogenic effect is unknown. Here, we show that TET1, a dioxygenase involved in cytosine demethylation, is downregulated in prostate and breast cancer tissues. TET1 depletion facilitates cell invasion, tumor growth, and cancer metastasis in prostate xenograft models and correlates with poor survival rates in breast cancer patients. Consistently, enforced expression of TET1 reduces cell invasion and breast xenograft tumor formation. Mechanistically, TET1 suppresses cell invasion through its dioxygenase and DNA binding activities. Furthermore, TET1 maintains the expression of tissue inhibitors of metalloproteinase (TIMP family proteins 2 and 3 by inhibiting their DNA methylation. Concurrent low expression of TET1 and TIMP2 or TIMP3 correlates with advanced node status in clinical samples. Together, these results illustrate a mechanism by which TET1 suppresses tumor development and invasion partly through downregulation of critical gene methylation.

  8. USP10 Antagonizes c-Myc Transcriptional Activation through SIRT6 Stabilization to Suppress Tumor Formation

    Directory of Open Access Journals (Sweden)

    Zhenghong Lin

    2013-12-01

    Full Text Available The reduced protein expression of SIRT6 tumor suppressor is involved in tumorigenesis. The molecular mechanisms underlying SIRT6 protein downregulation in human cancers remain unknown. Using a proteomic approach, we have identified the ubiquitin-specific peptidase USP10, another tumor suppressor, as one of the SIRT6-interacting proteins. USP10 suppresses SIRT6 ubiquitination to protect SIRT6 from proteasomal degradation. USP10 antagonizes the transcriptional activity of the c-Myc oncogene through SIRT6, as well as p53, to inhibit cell-cycle progression, cancer cell growth, and tumor formation. To support this conclusion, we detected significant reductions in both USP10 and SIRT6 protein expression in human colon cancers. Our study discovered crosstalk between two tumor-suppressive genes in regulating cell-cycle progression and proliferation and showed that dysregulated USP10 function promotes tumorigenesis through SIRT6 degradation.

  9. Analysis of Harmonics Suppression by Active Damping Control on Multi Slim DC-link Drives

    DEFF Research Database (Denmark)

    Yang, Feng; Máthé, Lászlo; Lu, Kaiyuan

    2016-01-01

    Compared with conventional dc-link drive, slim dc-link drive is expected to achieve lower cost and longer life time. However, harmonics distortion problem may occur in such drive systems. This paper proposes to use an active damping control method to suppress the harmonic distortion...... with the benefit of low cost and also low loss. A new analysis method, based on the frequency domain impedance model, is presented to explore the mechanism of harmonics suppression. Also, a general method is presented to build the impedance model of a PMSM drive system using Field Oriented Control (FOC) method....... Some design issues, including power levels, current control bandwidth and harmonic interaction, are discussed when the drive system is fed by a weak grid. Case studies on a two-drive system composed by two slim dc-link drive units are provided to verify the proposed analysis method....

  10. Study on Active Suppression Control of Drivetrain Oscillations in an Electric Vehicle

    Science.gov (United States)

    Huang, Lei; Cui, Ying

    2017-07-01

    Due to the low damping in a central driven electric vehicle and lack of passive damping mechanisms as compared with a conventional vehicle, the vehicle may endure torsional vibrations which may deteriorates the vehicle’s drivability. Thus active damping control strategy is required to reduce the undesirable oscillations in an EV. In this paper, the origin of the vibration and the design of a damping control method to suppress such oscillations to improve the drivability of an EV are studied. The traction motor torque that is given by the vehicle controller is adjusted according to the acceleration rate of the motor speed to attenuate the resonant frequency. Simulations and experiments are performed to validate the system. The results show that the proposed control system can effectively suppress oscillations and hence improve drivability.

  11. Sex differences in the acute locomotor response to methamphetamine in BALB/c mice.

    Science.gov (United States)

    Ohia-Nwoko, Odochi; Haile, Colin N; Kosten, Therese A

    2017-06-01

    Women use methamphetamine more frequently than men and are more vulnerable to its negative psychological effects. Rodent models have been an essential tool for evaluating the sex-dependent effects of psychostimulants; however, evidence of sex differences in the behavioral responses to methamphetamine in mice is lacking. In the present study, we investigated acute methamphetamine-induced (1mg/kg and 4mg/kg) locomotor activation in female and male BALB/c mice. We also evaluated whether basal locomotor activity was associated with the methamphetamine-induced locomotor response. The results indicated that female BALB/c mice displayed enhanced methamphetamine-induced locomotor activity compared to males, while basal locomotor activity was positively correlated with methamphetamine-induced activity in males, but not females. This study is the first to show sex-dependent locomotor effects of methamphetamine in BALB/c mice. Our observations emphasize the importance of considering sex when assessing behavioral responses to methamphetamine. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Chimaerin suppresses Rac1 activation at the apical membrane to maintain the cyst structure.

    Directory of Open Access Journals (Sweden)

    Shunsuke Yagi

    Full Text Available Epithelial organs are made of a well-polarized monolayer of epithelial cells, and their morphology is maintained strictly for their proper functions. Previously, we showed that Rac1 activation is suppressed at the apical membrane in the mature organoid, and that such spatially biased Rac1 activity is required for the polarity maintenance. Here we identify Chimaerin, a GTPase activating protein for Rac1, as a suppressor of Rac1 activity at the apical membrane. Depletion of Chimaerin causes over-activation of Rac1 at the apical membrane in the presence of hepatocyte growth factor (HGF, followed by luminal cell accumulation. Importantly, Chimaerin depletion did not inhibit extension formation at the basal membrane. These observations suggest that Chimaerin functions as the apical-specific Rac1 GAP to maintain epithelial morphology.

  13. Hybrid Active Filter with Variable Conductance for Harmonic Resonance Suppression in Industrial Power Systems

    DEFF Research Database (Denmark)

    Lee, Tzung-Lin; Wang, Yen-Ching; Li, Jian-Cheng

    2015-01-01

    Unintentional series and/or parallel resonances, due to the tuned passive filter and the line inductance, may result in severe harmonic distortion in the industrial power system. This paper presents a hybrid active filter to suppress harmonic resonance and reduce harmonic distortion as well......-tuned passive filter and an active filter in series connection, both dc voltage and kVA rating of the active filter are dramatically decreased compared with the pure shunt active filter. In real application, this feature is very attractive since the active power filter with fully power electronics is very....... The proposed hybrid filter is operated as variable harmonic conductance according to the voltage total harmonic distortion, so harmonic distortion can be reduced to an acceptable level in response to load change or parameter variation of power system. Since the hybrid filter is composed of a seventh...

  14. Endothelial cells suppress monocyte activation through secretion of extracellular vesicles containing antiinflammatory microRNAs.

    Science.gov (United States)

    Njock, Makon-Sébastien; Cheng, Henry S; Dang, Lan T; Nazari-Jahantigh, Maliheh; Lau, Andrew C; Boudreau, Emilie; Roufaiel, Mark; Cybulsky, Myron I; Schober, Andreas; Fish, Jason E

    2015-05-14

    The blood contains high concentrations of circulating extracellular vesicles (EVs), and their levels and contents are altered in several disease states, including cardiovascular disease. However, the function of circulating EVs, especially the microRNAs (miRNAs) that they contain, are poorly understood. We sought to determine the effect of secreted vesicles produced by quiescent endothelial cells (ECs) on monocyte inflammatory responses and to assess whether transfer of microRNAs occurs between these cells. We observed that monocytic cells cocultured (but not in contact) with ECs were refractory to inflammatory activation. Further characterization revealed that endothelium-derived EVs (EC-EVs) suppressed monocyte activation by enhancing immunomodulatory responses and diminishing proinflammatory responses. EVs isolated from mouse plasma also suppressed monocyte activation. Importantly, injection of EC-EVs in vivo repressed monocyte/macrophage activation, confirming our in vitro findings. We found that several antiinflammatory microRNAs were elevated in EC-EV-treated monocytes. In particular, miR-10a was transferred to monocytic cells from EC-EVs and could repress inflammatory signaling through the targeting of several components of the NF-κB pathway, including IRAK4. Our findings reveal that ECs secrete EVs that can modulate monocyte activation and suggest that altered EV secretion and/or microRNA content may affect vascular inflammation in the setting of cardiovascular disease. © 2015 by The American Society of Hematology.

  15. Antiosteoclastic Activity of Milk Thistle Extract after Ovariectomy to Suppress Estrogen Deficiency-Induced Osteoporosis

    Science.gov (United States)

    Kim, Jung-Lye; Kim, Yun-Ho; Kang, Min-Kyung; Gong, Ju-Hyun; Han, Seoung-Jun; Kang, Young-Hee

    2013-01-01

    Bone integrity abnormality and imbalance between bone formation by osteoblasts and bone resorption by osteoclasts are known to result in metabolic bone diseases such as osteoporosis. Silymarin-rich milk thistle extract (MTE) and its component silibinin enhanced alkaline phosphatase activity of osteoblasts but reduced tartrate-resistant acid phosphatase (TRAP) activity of osteoclasts. The osteoprotective effects of MTE were comparable to those of estrogenic isoflavone. Low-dose combination of MTE and isoflavone had a pharmacological synergy that may be useful for osteogenic activity. This study attempted to reveal the suppressive effects of MTE on bone loss. C57BL/6 female mice were ovariectomized (OVX) as a model for postmenopausal osteopenia and orally administered 10 mg/kg MTE or silibinin for 8 weeks. The sham-operated mice served as estrogen controls. The treatment of ovariectomized mice with nontoxic MTE and silibinin improved femoral bone mineral density and serum receptor activator of nuclear factor-κB ligand/osteoprotegerin ratio, an index of osteoclastogenic stimulus. In addition, the administration of MTE or silibinin inhibited femoral bone loss induced by ovariectomy and suppressed femoral TRAP activity and cathepsin K induction responsible for osteoclastogenesis and bone resorption. Collectively, oral dosage of MTE containing silibinin in the preclinical setting is effective in preventing estrogen deficiency-induced bone loss. PMID:23781510

  16. Principle and Control Design of Active Ground-Fault Arc Suppression Device for Full Compensation of Ground Current

    DEFF Research Database (Denmark)

    Wang, Wen; Zeng, Xiangjun; Yan, Lingjie

    2017-01-01

    . The commonly-used large-capacity reactive component may bring about overvoltage because of possible resonance with the distributed phase-to-ground capacitance. To solve these problems, an active ground-fault arc suppression device is presented. It employs a topology based on single-phase inverter to inject...... suppression without capacitive current detection. Its time-based feature also brings the benefit of fast response on ground-fault arc suppression. The principle of full current compensation is analyzed, together with the controller design method of the proposed device. Experiment on a prototype was carried......Traditional ground-fault arc suppression devices mainly deal with capacitive component of ground current and have weak effect on the active and harmonic ones, which limits the arc suppression performance. The capacitive current detection needed in them suffers from low accuracy and robustness...

  17. Persistence of locomotor-related interlimb reflex networks during walking after stroke.

    Science.gov (United States)

    Zehr, E Paul; Loadman, Pamela M

    2012-04-01

    Cutaneous nerve stimulation evokes coordinated and phase-modulated reflex output widely distributed to muscles of all four limbs during walking. Accessibility to this distributed network after stroke offers insight into the pathological changes and suggests utility for therapeutic applications. Here we examined muscles in both the more (MA) and less affected (LA) legs evoked by stimulation at the ankle and wrist during walking in chronic (>6 months post CVA) stroke. Stroke and control participants walked on a treadmill with a harness support system. Reflexes were evoked with trains of electrical stimuli delivered separately to the cutaneous superficial peroneal (SP; at the ankle) and superficial radial (SR; at the wrist) nerves. Background locomotor and reflex EMG were phase-averaged across the gait cycle and analyzed off line. Locomotor background muscle activation patterns were altered bilaterally in stroke, as compared with control. Phase-dependent modulation of interlimb cutaneous reflexes was found in both stroke and control subjects with stimulation of each nerve, but responses were blunted in stroke. Reflex reversal in tibialis anterior (TA) at heel strike with SP nerve stimulation was present in both groups. Notably, SR nerve stimulation produced facilitation during the swing-to-stance transition in the TA and suppression of MG in the MA leg during stance. Interlimb cutaneous inputs may access coordinated reflex pathways in the MA limb during walking after stroke. Importantly activation in these pathways could provoke responses to counter foot drop during swing phase of walking. Additionally, our data support the perspective that there is no "unaffected" side after stroke and that caution should be used when interpreting the LA side as "control" after stroke. The presence of functionally-relevant interlimb cutaneous reflexes in the MA leg presents a substrate that may be strengthened by rehabilitation. Copyright © 2011 International Federation of Clinical

  18. Ritmos de actividad locomotora y uso de las cuevas en condiciones seminaturales en Ctenomys talarum (Rodentia, Octodontidae Rhythms of locomotor activity and burrow use under seminatural conditions in Ctenomys talarum (Rodentia, Octodontidae

    Directory of Open Access Journals (Sweden)

    FACUNDO LUNA

    2000-03-01

    Full Text Available Ctenomys es un género de roedores subterráneos que vive en sistemas de galerías cerrados a la superficie del suelo y por lo tanto lleva a cabo la mayoría de sus actividades en ausencia de luz. Sin embargo a diferencia de otros roedores subterráneos sus salidas a la superficie son frecuentes. En este trabajo fueron evaluadas, en Ctenomys talarum (Thomas, 1898 la existencia y las características de los ritmos locomotores de actividad para distintas condiciones experimentales. Además, fueron analizadas la permanencia y preferencia por distintos sectores del sistema de galerías. El 25 % de los individuos de C. talarum analizados, para las distintas condiciones de fotoperiodo y temperatura ambiente evaluadas, mostraron actividad rítmica. Por otra parte, los individuos no presentaron un patrón generalizado de permanencia y preferencia por sectores definidos en el sistema de galeríasCtenomys are subterranean rodents that perform most of their daily activities in dark, thermally stable burrow systems. In this paper the dependence of Ctenomys talarum (Thomas, 1898 activity rhythms on either photoperiod and ambient temperature was analyzed, as well as permanency and preference for different sectors of a burrow system. 25 % of the individuals showed rhythmicity in their activities. Thus, luminous stimuli and ambient temperature did not affect activity pattern in this species. Furthermore, individuals of C. talarum did not show any generalized pattern of preference and permanency on defined sectors of the artificial burrow system

  19. Fear conditioning suppresses large-conductance calcium-activated potassium channels in lateral amygdala neurons.

    Science.gov (United States)

    Sun, P; Zhang, Q; Zhang, Y; Wang, F; Wang, L; Yamamoto, R; Sugai, T; Kato, N

    2015-01-01

    It was previously shown that depression-like behavior is accompanied with suppression of the large-conductance calcium activated potassium (BK) channel in cingulate cortex pyramidal cells. To test whether BK channels are also involved in fear conditioning, we studied neuronal properties of amygdala principal cells in fear conditioned mice. After behavior, we made brain slices containing the amygdala, the structure critically relevant to fear memory. The resting membrane potential in lateral amygdala (LA) neurons obtained from fear conditioned mice (FC group) was more depolarized than in neurons from naïve controls. The frequencies of spikes evoked by current injections were higher in neurons from FC mice, demonstrating that excitability of LA neurons was elevated by fear conditioning. The depolarization in neurons from FC mice was shown to depend on BK channels by using the BK channel blocker charybdotoxin. Suppression of BK channels in LA neurons from the FC group was further confirmed on the basis of the spike width, since BK channels affect the descending phase of spikes. Spikes were broader in the FC group than those in the naïve control in a manner dependent on BK channels. Consistently, quantitative real-time PCR revealed a decreased expression of BK channel mRNA. The present findings suggest that emotional disorder manifested in the forms of fear conditioning is accompanied with BK channel suppression in the amygdala, the brain structure critical to this emotional disorder. Copyright © 2014 Elsevier Inc. All rights reserved.

  20. IKKα Activation of NOTCH LinksTumorigenesis via FOXA2 Suppression

    Science.gov (United States)

    Liu, Mo; Lee, Dung-Fang; Chen, Chun-Te; Yen, Chia-Jui; Li, Long-Yuan; Lee, Hong-Jen; Chang, Chun-Ju; Chang, Wei-Chao; Hsu, Jung-Mao; Kuo, Hsu-Ping; Xia, Weiya; Wei, Yongkun; Chiu, Pei-Chun; Chou, Chao-Kai; Du, Yi; Dhar, Debanjan; Karin, Michael; Chen, Chung-Hsuan; Hung, Mien-Chie

    2011-01-01

    SUMMARY Pro-inflammatory cytokine TNFα plays critical roles in promoting malignant cell proliferation, angiogenesis, and tumor metastasis in many cancers. However, the mechanism of TNFα-mediated tumor development remains unclear. Here, we show that IKKα, an important downstream kinase of TNFα, interacts with and phosphorylates FOXA2 at S107/ S111, thereby suppressing FOXA2 transactivation activity, leading to decreased NUMB expression and further activates the downstream NOTCH pathway and promotes cell proliferation and tumorigenesis. Moreover, we found that levels of IKKα, pFOXA2 (S107/111), and activated NOTCH1 were significantly higher in hepatocellular carcinoma tumors than in normal liver tissues and that pFOXA2 (S107/111) expression was positively correlated with IKKα and activated NOTCH1 expression in tumor tissues. Therefore, dysregulation of NUMB-mediated suppression of NOTCH1 by TNFα/IKKα-associated FOXA2 inhibition likely contributes to inflammation-mediated cancer pathogenesis. Here, we report TNFα/IKKα/FOXA2/NUMB/NOTCH1 pathway that is critical for inflammation-mediated tumorigenesis and may provide a target for clinical intervention in human cancer. PMID:22196886

  1. The deacetylase Sirt6 activates the acetyltransferase GCN5 and suppresses hepatic gluconeogenesis.

    Science.gov (United States)

    Dominy, John E; Lee, Yoonjin; Jedrychowski, Mark P; Chim, Helen; Jurczak, Michael J; Camporez, Joao Paulo; Ruan, Hai-Bin; Feldman, Jessica; Pierce, Kerry; Mostoslavsky, Raul; Denu, John M; Clish, Clary B; Yang, Xiaoyong; Shulman, Gerald I; Gygi, Steven P; Puigserver, Pere

    2012-12-28

    Hepatic glucose production (HGP) maintains blood glucose levels during fasting but can also exacerbate diabetic hyperglycemia. HGP is dynamically controlled by a signaling/transcriptional network that regulates the expression/activity of gluconeogenic enzymes. A key mediator of gluconeogenic gene transcription is PGC-1α. PGC-1α's activation of gluconeogenic gene expression is dependent upon its acetylation state, which is controlled by the acetyltransferase GCN5 and the deacetylase Sirt1. Nevertheless, whether other chromatin modifiers-particularly other sirtuins-can modulate PGC-1α acetylation is currently unknown. Herein, we report that Sirt6 strongly controls PGC-1α acetylation. Surprisingly, Sirt6 induces PGC-1α acetylation and suppresses HGP. Sirt6 depletion decreases PGC-1α acetylation and promotes HGP. These acetylation effects are GCN5 dependent: Sirt6 interacts with and modifies GCN5, enhancing GCN5's activity. Lepr(db/db) mice, an obese/diabetic animal model, exhibit reduced Sirt6 levels; ectopic re-expression suppresses gluconeogenic genes and normalizes glycemia. Activation of hepatic Sirt6 may therefore be therapeutically useful for treating insulin-resistant diabetes. Copyright © 2012 Elsevier Inc. All rights reserved.

  2. Effects of Arc/Arg3.1 gene deletion on rhythmic synchronization of hippocampal CA1 neurons during locomotor activity and sleep.

    NARCIS (Netherlands)

    Malkki, H.A.I.; Mertens, P.E.C.; Lankelma, J.V.; Vinck, M.; van Schalkwijk, F.J.; van Mourik-Donga, L.B.; Battaglia, F.P.; Mahlke, C.; Kuhl, D.; Pennartz, C.M.A.

    2016-01-01

    The activity-regulated cytoskeletal-associated protein/activity regulated gene (Arc/Arg3.1) is crucial for long-term synaptic plasticity and memory formation. However, the neurophysiological substrates of memory deficits occurring in the absence of Arc/Arg3.1 are unknown. We compared hippocampal CA1

  3. Effects of insemination and blood-feeding on locomotor activity of Aedes albopictus and Aedes aegypti (Diptera: Culicidae) females under laboratory conditions

    OpenAIRE

    Lima-Camara, Tamara N; Lima, José B P; Bruno, Rafaela V; Peixoto, Alexandre A

    2014-01-01

    Abstract Background Dengue is an arbovirus disease transmitted by two Aedes mosquitoes: Ae. aegypti and Ae. albopictus. Virgin females of these two species generally show a bimodal and diurnal pattern of activity, with early morning and late afternoon peaks. Although some studies on the flight activity of virgin, inseminated and blood-fed Ae. aegypti females have been carried out under laboratory conditions, little...

  4. Macrophage activation induced by Brucella DNA suppresses bacterial intracellular replication via enhancing NO production.

    Science.gov (United States)

    Liu, Ning; Wang, Lin; Sun, Changjiang; Yang, Li; Tang, Bin; Sun, Wanchun; Peng, Qisheng

    2015-12-01

    Brucella DNA can be sensed by TLR9 on endosomal membrane and by cytosolic AIM2-inflammasome to induce proinflammatory cytokine production that contributes to partially activate innate immunity. Additionally, Brucella DNA has been identified to be able to act as a major bacterial component to induce type I IFN. However, the role of Brucella DNA in Brucella intracellular growth remains unknown. Here, we showed that stimulation with Brucella DNA promote macrophage activation in TLR9-dependent manner. Activated macrophages can suppresses wild type Brucella intracellular replication at early stage of infection via enhancing NO production. We also reported that activated macrophage promotes bactericidal function of macrophages infected with VirB-deficient Brucella at the early or late stage of infection. This study uncovers a novel function of Brucella DNA, which can help us further elucidate the mechanism of Brucella intracellular survival. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. PCAF Improves Glucose Homeostasis by Suppressing the Gluconeogenic Activity of PGC-1α

    Directory of Open Access Journals (Sweden)

    Cheng Sun

    2014-12-01

    Full Text Available PGC-1α plays a central role in hepatic gluconeogenesis and has been implicated in the onset of type 2 diabetes. Acetylation is an important posttranslational modification for regulating the transcriptional activity of PGC-1α. Here, we show that PCAF is a pivotal acetyltransferase for acetylating PGC-1α in both fasted and diabetic states. PCAF acetylates two lysine residues K328 and K450 in PGC-1α, which subsequently triggers its proteasomal degradation and suppresses its transcriptional activity. Adenoviral-mediated expression of PCAF in the obese mouse liver greatly represses gluconeogenic enzyme activation and glucose production and improves glucose homeostasis and insulin sensitivity. Moreover, liver-specific knockdown of PCAF stimulates PGC-1α activity, resulting in an increase in blood glucose and hepatic glucose output. Our results suggest that PCAF might be a potential pharmacological target for developing agents against metabolic disorders associated with hyperglycemia, such as obesity and diabetes.

  6. Locomotor rehabilitation in a complex virtual environment.

    Science.gov (United States)

    Fung, J; Malouin, F; McFadyen, B J; Comeau, F; Lamontagne, A; Chapdelaine, S; Beaudoin, C; Laurendeau, D; Hughey, L; Richards, C L

    2004-01-01

    Virtual reality (VR) technology offers a new and safe way to increase practice time and provide the varied environments and constraints needed to optimize locomotor training. Our specific objectives are (1) to create a virtual environment (VE) coupled with a self-paced treadmill for locomotor training; (2) to compare temporal and distance measurements of gait during treadmill walking while looking at different scenarios of VE; and (3) to develop a protocol optimized for the training of locomotor disorders after stroke. A motorized treadmill was mounted on a six-degree-of-freedom motion platform. VEs were created using commercial software (SoftImage) and projected on a large screen, while system control was administered through the CAREN software (Motek BV). The instantaneous treadmill speed and scene progression were servo-controlled. Preliminary results show that healthy subjects are able to have full control of their own walking speed both on the treadmill and within the virtual scene, while experiencing a strong sense of presence. A street crossing training protocol has been developed for locomotor training. It is expected that locomotor training with increasingly complex VEs will allow persons with stroke to increase progressively their locomotor capacity, as required and entrained by the VE.

  7. Study of exteroceptive suppression of voluntary muscular activity in healthy volunteers and patients with paroxysmal neuropathic pain.

    Science.gov (United States)

    Gordeev, S A; Turbina, L G; Shtang, O M

    2014-07-01

    The exteroceptive suppression of voluntary electromyographic activity of the masseter and temporal muscles was studied in healthy volunteers and patients with paroxysmal neuropathic pain (trigeminal neuralgia). The latent period of the exteroceptive suppression was prolonged and the duration of its late fragment was shortened in the patients in comparison with normal subjects. A short exteroceptive suppression period in patients with trigeminal neuralgia reflected deficient activity of inhibitory interneurons of the reflector loop and excessive activity of the antinociceptive system of the brain stem, while prolongation of the latent period reflected prolongation of inhibitory interneurons activation. A direct correlation between the degree of changes in the exteroceptive suppression parameters and pain intensity, evaluated by the patients by the visual analog scale, was detected.

  8. Functional connectivity in raphé-pontomedullary circuits supports active suppression of breathing during hypocapnic apnea

    Science.gov (United States)

    Nuding, Sarah C.; Segers, Lauren S.; Iceman, Kimberly E.; O'Connor, Russell; Dean, Jay B.; Bolser, Donald C.; Baekey, David M.; Dick, Thomas E.; Shannon, Roger; Morris, Kendall F.

    2015-01-01

    Hyperventilation is a common feature of disordered breathing. Apnea ensues if CO2 drive is sufficiently reduced. We tested the hypothesis that medullary raphé, ventral respiratory column (VRC), and pontine neurons have functional connectivity and persistent or evoked activities appropriate for roles in the suppression of drive and rhythm during hyperventilation and apnea. Phrenic nerve activity, arterial blood pressure, end-tidal CO2, and other parameters were monitored in 10 decerebrate, vagotomized, neuromuscularly-blocked, and artificially ventilated cats. Multielectrode arrays recorded spiking activity of 649 neurons. Loss and return of rhythmic activity during passive hyperventilation to apnea were identified with the S-transform. Diverse fluctuating activity patterns were recorded in the raphé-pontomedullary respiratory network during the transition to hypocapnic apnea. The firing rates of 160 neurons increased during apnea; the rates of 241 others decreased or stopped. VRC inspiratory neurons were usually the last to cease firing or lose rhythmic activity during the transition to apnea. Mayer wave-related oscillations (0.04–0.1 Hz) in firing rate were also disrupted during apnea. Four-hundred neurons (62%) were elements of pairs with at least one hyperventilation-responsive neuron and a correlational signature of interaction identified by cross-correlation or gravitational clustering. Our results support a model with distinct groups of chemoresponsive raphé neurons contributing to hypocapnic apnea through parallel processes that incorporate disfacilitation and active inhibition of inspiratory motor drive by expiratory neurons. During apnea, carotid chemoreceptors can evoke rhythm reemergence and an inspiratory shift in the balance of reciprocal inhibition via suppression of ongoing tonic expiratory neuron activity. PMID:26203111

  9. Opiate-induced suppression of rat hypoglossal motoneuron activity and its reversal by ampakine therapy.

    Directory of Open Access Journals (Sweden)

    Amanda R Lorier

    2010-01-01

    Full Text Available Hypoglossal (XII motoneurons innervate tongue muscles and are vital for maintaining upper-airway patency during inspiration. Depression of XII nerve activity by opioid analgesics is a significant clinical problem, but underlying mechanisms are poorly understood. Currently there are no suitable pharmacological approaches to counter opiate-induced suppression of XII nerve activity while maintaining analgesia. Ampakines accentuate alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA receptor responses. The AMPA family of glutamate receptors mediate excitatory transmission to XII motoneurons. Therefore the objectives were to determine whether the depressant actions of mu-opioid receptor activation on inspiratory activity includes a direct inhibitory action at the inspiratory premotoneuron to XII motoneuron synapse, and to identify underlying mechanism(s. We then examined whether ampakines counteract opioid-induced depression of XII motoneuron activity.A medullary slice preparation from neonatal rat that produces inspiratory-related output in vitro was used. Measurements of inspiratory burst amplitude and frequency were made from XII nerve roots. Whole-cell patch recordings from XII motoneurons were used to measure membrane currents and synaptic events. Application of the mu-opioid receptor agonist, DAMGO, to the XII nucleus depressed the output of inspiratory XII motoneurons via presynaptic inhibition of excitatory glutamatergic transmission. Ampakines (CX614 and CX717 alleviated DAMGO-induced depression of XII MN activity through postsynaptic actions on XII motoneurons.The inspiratory-depressant actions of opioid analgesics include presynaptic inhibition of XII motoneuron output. Ampakines counteract mu-opioid receptor-mediated depression of XII motoneuron inspiratory activity. These results suggest that ampakines may be beneficial in countering opiate-induced suppression of XII motoneuron activity and resultant impairment of airway patency.

  10. Scutellarin Suppresses NLRP3 Inflammasome Activation in Macrophages and Protects Mice against Bacterial Sepsis.

    Science.gov (United States)

    Liu, Yi; Jing, Yan-Yun; Zeng, Chen-Ying; Li, Chen-Guang; Xu, Li-Hui; Yan, Liang; Bai, Wen-Jing; Zha, Qing-Bing; Ouyang, Dong-Yun; He, Xian-Hui

    2017-01-01

    The NLRP3 inflammasome plays a critical role in mediating the innate immune defense against pathogenic infections, but aberrant activation of NLRP3 inflammasome has been linked to a variety of inflammatory diseases. Thus targeting the NLRP3 inflammasome represents a promising therapeutic for the treatment of such diseases. Scutellarin is a flavonoid isolated from Erigeron breviscapus (Vant.) Hand.-Mazz. and has been reported to exhibit potent anti-inflammatory activities, but the underlying mechanism is only partly understood. In this study, we aimed to investigate whether scutellarin could affect the activation of NLRP3 inflammasome in macrophages. The results showed that scutellarin dose-dependently reduced caspase-1 activation and decreased mature interleukin-1β (IL-1β) release in lipopolysaccharide (LPS)-primed macrophages upon ATP or nigericin stimulation, indicating that scutellarin inhibited NLRP3 inflammasome activation in macrophages. Consistent with this, scutellarin also suppressed pyroptotic cell death in LPS-primed macrophages treated with ATP or nigericin. ATP or nigericin-induced ASC speck formation and its oligomerization were blocked by scutellarin pre-treatment. Intriguingly, scutellarin augmented PKA-specific phosphorylation of NLRP3 in LPS-primed macrophages, which was completely blocked by selective PKA inhibitor H89, suggesting that PKA signaling had been involved in the action of scutellarin to suppress NLRP3 inflammasome activation. Supporting this, the inhibitory effect of scutellarin on NLRP3 inflammasome activation was completely counteracted by H89 or adenyl cyclase inhibitor MDL12330A. As NLRP3-dependent release of IL-1β has a critical role in sepsis, the in vivo activity of scutellarin was assayed in a mouse model of bacterial sepsis, which was established by intraperitoneally injection of a lethal dose of viable Escherichia coli . Oral administration of scutellarin significantly improved the survival of mice with bacterial sepsis

  11. Scutellarin Suppresses NLRP3 Inflammasome Activation in Macrophages and Protects Mice against Bacterial Sepsis

    Directory of Open Access Journals (Sweden)

    Yi Liu

    2018-01-01

    Full Text Available The NLRP3 inflammasome plays a critical role in mediating the innate immune defense against pathogenic infections, but aberrant activation of NLRP3 inflammasome has been linked to a variety of inflammatory diseases. Thus targeting the NLRP3 inflammasome represents a promising therapeutic for the treatment of such diseases. Scutellarin is a flavonoid isolated from Erigeron breviscapus (Vant. Hand.-Mazz. and has been reported to exhibit potent anti-inflammatory activities, but the underlying mechanism is only partly understood. In this study, we aimed to investigate whether scutellarin could affect the activation of NLRP3 inflammasome in macrophages. The results showed that scutellarin dose-dependently reduced caspase-1 activation and decreased mature interleukin-1β (IL-1β release in lipopolysaccharide (LPS-primed macrophages upon ATP or nigericin stimulation, indicating that scutellarin inhibited NLRP3 inflammasome activation in macrophages. Consistent with this, scutellarin also suppressed pyroptotic cell death in LPS-primed macrophages treated with ATP or nigericin. ATP or nigericin-induced ASC speck formation and its oligomerization were blocked by scutellarin pre-treatment. Intriguingly, scutellarin augmented PKA-specific phosphorylation of NLRP3 in LPS-primed macrophages, which was completely blocked by selective PKA inhibitor H89, suggesting that PKA signaling had been involved in the action of scutellarin to suppress NLRP3 inflammasome activation. Supporting this, the inhibitory effect of scutellarin on NLRP3 inflammasome activation was completely counteracted by H89 or adenyl cyclase inhibitor MDL12330A. As NLRP3-dependent release of IL-1β has a critical role in sepsis, the in vivo activity of scutellarin was assayed in a mouse model of bacterial sepsis, which was established by intraperitoneally injection of a lethal dose of viable Escherichia coli. Oral administration of scutellarin significantly improved the survival of mice with

  12. Activation of peroxisome proliferator-activated receptor-α (PPARα) suppresses postprandial lipidemia through fatty acid oxidation in enterocytes

    International Nuclear Information System (INIS)

    Kimura, Rino; Takahashi, Nobuyuki; Murota, Kaeko; Yamada, Yuko; Niiya, Saori; Kanzaki, Noriyuki; Murakami, Yoko; Moriyama, Tatsuya; Goto, Tsuyoshi; Kawada, Teruo

    2011-01-01

    Highlights: → PPARα activation increased mRNA expression levels of fatty acid oxidation-related genes in human intestinal epithelial Caco-2 cells. → PPARα activation also increased oxygen consumption rate and CO 2 production and decreased secretion of triglyceride and ApoB from Caco-2 cells. → Orally administration of bezafibrate increased mRNA expression levels of fatty acid oxidation-related genes and CO 2 production in small intestinal epithelial cells. → Treatment with bezafibrate decreased postprandial serum concentration of triglyceride after oral injection of olive oil in mice. → It suggested that intestinal lipid metabolism regulated by PPARα activation suppresses postprandial lipidemia. -- Abstract: Activation of peroxisome proliferator-activated receptor (PPAR)-α which regulates lipid metabolism in peripheral tissues such as the liver and skeletal muscle, decreases circulating lipid levels, thus improving hyperlipidemia under fasting conditions. Recently, postprandial serum lipid levels have been found to correlate more closely to cardiovascular diseases than fasting levels, although fasting hyperlipidemia is considered an important risk of cardiovascular diseases. However, the effect of PPARα activation on postprandial lipidemia has not been clarified. In this study, we examined the effects of PPARα activation in enterocytes on lipid secretion and postprandial lipidemia. In Caco-2 enterocytes, bezafibrate, a potent PPARα agonist, increased mRNA expression levels of fatty acid oxidation-related genes, such as acyl-CoA oxidase, carnitine palmitoyl transferase, and acyl-CoA synthase, and oxygen consumption rate (OCR) and suppressed secretion levels of both triglycerides and apolipoprotein B into the basolateral side. In vivo experiments revealed that feeding high-fat-diet containing bezafibrate increased mRNA expression levels of fatty acid oxidation-related genes and production of CO 2 and acid soluble metabolites in enterocytes. Moreover

  13. Multirate Flutter Suppression System Design for the Benchmark Active Controls Technology Wing. Part 2; Methodology Application Software Toolbox

    Science.gov (United States)

    Mason, Gregory S.; Berg, Martin C.; Mukhopadhyay, Vivek

    2002-01-01

    To study the effectiveness of various control system design methodologies, the NASA Langley Research Center initiated the Benchmark Active Controls Project. In this project, the various methodologies were applied to design a flutter suppression system for the Benchmark Active Controls Technology (BACT) Wing. This report describes the user's manual and software toolbox developed at the University of Washington to design a multirate flutter suppression control law for the BACT wing.

  14. Activation of the aryl hydrocarbon receptor suppresses sensitization in a mouse peanut allergy model.

    Science.gov (United States)

    Schulz, V J; Smit, J J; Willemsen, K J; Fiechter, D; Hassing, I; Bleumink, R; Boon, L; van den Berg, M; van Duursen, M B M; Pieters, R H H

    2011-10-01

    Food allergy is an increasing health problem in Western countries. Previously, it has been shown that the intensity of food allergic reactions can be regulated by regulatory T (T(reg)) cells. In addition, it has been shown that activation of the aryl hydrocarbon receptor (AhR) regulates T-cell responses by induction of T(reg) cells. Therefore, we hypothesized that activation of the AhR pathway can suppress development of food allergic responses through the induction of T(reg) cells. This was investigated by using a mouse model for peanut allergy. C3H/HeOuJ mice (AhR(b)(-2)) were sensitized to peanut by administering peanut extract (PE) by gavage in the presence of cholera toxin and were treated with the prototypical AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (0.6, 1.7, 5, and 15 μg/kg body weight) on days 3 and 11 orally. The functional role of CD4(+)CD25(+)Foxp3(+) T(reg) cells was investigated by depleting these cells with anti-CD25 mAb during sensitization to PE. TCDD treatment dose dependently suppressed sensitization to peanut (PE-specific IgE, IgG1, and IgG2a and PE-induced IL-5, IL-10, and IL-13, respectively). The percentage, but not the number, of CD4(+)CD25(+)Foxp3(+) T(reg) cells dose dependently increased by AhR activation in both spleen and mesenteric lymph nodes. Depletion of CD4(+)CD25(+)Foxp3(+) T(reg) cells markedly reversed the suppressive effect of TCDD on PE-specific antibody levels and PE-induced IL-5, IL-10, and IL-13 cytokine production. Present data demonstrate for the first time that activation of the AhR by TCDD suppressed the development of Th2-mediated food allergic responses. A functional shift within the CD4(+) cell population toward CD4(+)CD25(+)Foxp3(+) T(reg) cells appeared to underlie this effect. This suggests that the AhR pathway might provide potential therapeutic targets to treat food allergic diseases.

  15. Induction of anergy or active suppression following oral tolerance is determined by antigen dosage.

    OpenAIRE

    Friedman, A; Weiner, H L

    1994-01-01

    Oral tolerance was generated to hen egg white lysozyme in the mouse or to guinea pig myelin basic protein in the rat by a low-dose (1 mg) or a high-dose (5-20 mg) feeding regimen. High doses of antigen induced tolerance characterized by anergy with little or no active suppression and increased secretion of interleukin 4 (IL-4). Anergy was shown by an increase in frequency of IL-2-secreting cells following culture in recombinant IL-2. Low doses of antigen induced tolerance characterized by ant...

  16. Cholesterol synthesis inhibitor RO 48-8071 suppresses transcriptional activity of human estrogen and androgen receptor.

    Science.gov (United States)

    Mafuvadze, Benford; Liang, Yayun; Hyder, Salman M

    2014-10-01

    Breast cancer cells express enzymes that convert cholesterol, the synthetic precursor of steroid hormones, into estrogens and androgens, which then drive breast cancer cell proliferation. In the present study, we sought to determine whether oxidosqualene cyclase (OSC), an enzyme in the cholesterol biosynthetic pathway, may be targeted to suppress progression of breast cancer cells. In previous studies, we showed that the OSC inhibitor RO 48-8071 (RO) may be a ligand which could potentially be used to control the progression of estrogen receptor-α (ERα)-positive breast cancer cells. Herein, we showed, by real-time PCR analysis of mRNA from human breast cancer biopsies, no significant differences in OSC expression at various stages of disease, or between tumor and normal mammary cells. Since the growth of hormone-responsive tumors is ERα-dependent, we conducted experiments to determine whether RO affects ERα. Using mammalian cells engineered to express human ERα or ERβ protein, together with an ER-responsive luciferase promoter, we found that RO dose-dependently inhibited 17β-estradiol (E2)-induced ERα responsive luciferase activity (IC50 value, ~10 µM), under conditions that were non-toxic to the cells. RO was less effective against ERβ-induced luciferase activity. Androgen receptor (AR) mediated transcriptional activity was also reduced by RO. Notably, while ERα activity was reduced by atorvastatin, the HMG-CoA reductase inhibitor did not influence AR activity, showing that RO possesses broader antitumor properties. Treatment of human BT-474 breast cancer cells with RO reduced levels of estrogen-induced PR protein, confirming that RO blocks ERα activity in tumor cells. Our findings demonstrate that an important means by which RO suppresses hormone-dependent growth of breast cancer cells is through its ability to arrest the biological activity of ERα. This warrants further investigation of RO as a potential therapeutic agent for use against hormone

  17. Cellulase activity as a mechanism for suppression of phytophthora root rot in mulches.

    Science.gov (United States)

    Richter, Brantlee Spakes; Ivors, Kelly; Shi, Wei; Benson, D M

    2011-02-01

    Wood-based mulches are used in avocado production and are being tested on Fraser fir for reduction of Phytophthora root rot, caused by Phytophthora cinnamomi. Research with avocado has suggested a role of microbial cellulase enzymes in pathogen suppression through effects on the cellulosic cell walls of Phytophthora. This work was conducted to determine whether cellulase activity could account for disease suppression in mulch systems. A standard curve was developed to correlate cellulase activity in mulches with concentrations of a cellulase product. Based on this curve, cellulase activity in mulch samples was equivalent to a cellulase enzyme concentration of 25 U ml(-1) or greater of product. Sustained exposure of P. cinnamomi to cellulase at 10 to 50 U ml(-1) significantly reduced sporangia production, but biomass was only reduced with concentrations over 100 U ml(-1). In a lupine bioassay, cellulase was applied to infested soil at 100 or 1,000 U ml(-1) with three timings. Cellulase activity diminished by 47% between 1 and 15 days after application. Cellulase applied at 100 U ml(-1) 2 weeks before planting yielded activity of 20.08 μmol glucose equivalents per gram of soil water (GE g(-1) aq) at planting, a level equivalent to mulch samples. Cellulase activity at planting ranged from 3.35 to 48.67 μmol GE g(-1) aq, but no treatment significantly affected disease progress. Based on in vitro assays, cellulase activity in mulch was sufficient to impair sporangia production of P. cinnamomi, but not always sufficient to impact vegetative biomass.

  18. Magnetic suppression of turbulence and the star formation activity of molecular clouds

    Science.gov (United States)

    Zamora-Avilés, Manuel; Vázquez-Semadeni, Enrique; Körtgen, Bastian; Banerjee, Robi; Hartmann, Lee

    2018-03-01

    We present magnetohydrodynamic simulations aimed at studying the effect of the magnetic suppression of turbulence (generated through various instabilities during the formation of molecular clouds by converging) on the subsequent star formation (SF) activity. We study four magnetically supercritical models with magnetic field strengths B = 0, 1, 2, and 3 μG (corresponding to mass-to-flux ratios of ∞, 4.76, 2.38, and 1.59 times the critical value), with the magnetic field, initially being aligned with the flows. We find that, for increasing magnetic field strength, the clouds formed tend to be more massive, denser, less turbulent, and with higher SF activity. This causes the onset of SF activity in the non-magnetic or more weakly magnetized cases to be delayed by a few Myr in comparison to the more strongly magnetized cases. We attribute this behaviour to the suppression of the non-linear thin shell instability (NTSI) by the magnetic field, previously found by Heitsch and coworkers. This result is contrary to the standard notion that the magnetic field provides support to the clouds, thus reducing their star formation rate. However, our result is a completely non-linear one, and could not be foreseen from simple linear considerations.

  19. Folliculin contributes to VHL tumor suppressing activity in renal cancer through regulation of autophagy.

    Directory of Open Access Journals (Sweden)

    Prabhat Bastola

    Full Text Available Von Hippel-Lindau tumor suppressor (VHL is lost in the majority of clear cell renal cell carcinomas (ccRCC. Folliculin (FLCN is a tumor suppressor whose function is lost in Birt-Hogg-Dubé syndrome (BHD, a disorder characterized by renal cancer of multiple histological types including clear cell carcinoma, cutaneous fibrofolliculoma, and pneumothorax. Here we explored whether there is connection between VHL and FLCN in clear cell renal carcinoma cell lines and tumors. We demonstrate that VHL regulates expression of FLCN at the mRNA and protein levels in RCC cell lines, and that FLCN protein expression is decreased in human ccRCC tumors with VHL loss, as compared with matched normal kidney tissue. Knockdown of FLCN results in increased formation of tumors by RCC cells with wild-type VHL in orthotopic xenografts in nude mice, an indication that FLCN plays a role in the tumor-suppressing activity of VHL. Interestingly, FLCN, similarly to VHL, is necessary for the activity of LC3C-mediated autophagic program that we have previously characterized as contributing to the tumor suppressing activity of VHL. The results show the existence of functional crosstalk between two major tumor suppressors in renal cancer, VHL and FLCN, converging on regulation of autophagy.

  20. Suppression of human immunodeficiency virus type 1 activity in vitro by oligonucleotides which form intramolecular tetrads.

    Science.gov (United States)

    Rando, R F; Ojwang, J; Elbaggari, A; Reyes, G R; Tinder, R; McGrath, M S; Hogan, M E

    1995-01-27

    An oligonucleotide (I100-15) composed of only deoxyguanosine and thymidine was able to inhibit human immunodeficiency virus type-1 (HIV-1) in culture assay systems. I100-15 did not block virus entry into cells but did reduce viral-specific transcripts. As assessed by NMR and polyacrylamide gel methods, I100-15 appears to form a structure in which two stacked guanosine tetrads are connected by three two-base long loops. Structure/activity experiments indicated that formation of intramolecular guanosine tetrads was necessary to achieve maximum antiviral activity. The single deoxyguanosine nucleotide present in each loop was found to be extremely important for the overall antiviral activity. The toxicity of I100-15 was determined to be well above the 50% effective dose (ED50) in culture which yielded a high therapeutic index (> 100). The addition of a cholesterol moiety to the 3' terminus of I100-15 (I100-23) reduced the ED50 value to less than 50 nM (from 0.12 microM for I100-15) and increased the duration of viral suppression to greater than 21 days (versus 7-10 days for I100-15) after removal of the drug from infected cell cultures. The favorable therapeutic index of such molecules coupled with the prolonged suppression of HIV-1, suggest that such compounds further warrant investigation as potential therapeutic agents.

  1. Locomotor adaptation to a soleus EMG-controlled antagonistic exoskeleton

    Science.gov (United States)

    Kinnaird, Catherine R.; Ferris, Daniel P.

    2013-01-01

    Locomotor adaptation in humans is not well understood. To provide insight into the neural reorganization that occurs following a significant disruption to one's learned neuromuscular map relating a given motor command to its resulting muscular action, we tied the mechanical action of a robotic exoskeleton to the electromyography (EMG) profile of the soleus muscle during walking. The powered exoskeleton produced an ankle dorsiflexion torque proportional to soleus muscle recruitment thus limiting the soleus' plantar flexion torque capability. We hypothesized that neurologically intact subjects would alter muscle activation patterns in response to the antagonistic exoskeleton by decreasing soleus recruitment. Subjects practiced walking with the exoskeleton for two 30-min sessions. The initial response to the perturbation was to “fight” the resistive exoskeleton by increasing soleus activation. By the end of training, subjects had significantly reduced soleus recruitment resulting in a gait pattern with almost no ankle push-off. In addition, there was a trend for subjects to reduce gastrocnemius recruitment in proportion to the soleus even though only the soleus EMG was used to control the exoskeleton. The results from this study demonstrate the ability of the nervous system to recalibrate locomotor output in response to substantial changes in the mechanical output of the soleus muscle and associated sensory feedback. This study provides further evidence that the human locomotor system of intact individuals is highly flexible and able to adapt to achieve effective locomotion in response to a broad range of neuromuscular perturbations. PMID:23307949

  2. Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis

    Energy Technology Data Exchange (ETDEWEB)

    Anastasiou, Dimitrios; Yu, Yimin; Israelsen, William J.; Jiang, Jian-Kang; Boxer, Matthew B.; Hong, Bum Soo; Tempel, Wolfram; Dimov, Svetoslav; Shen, Min; Jha, Abhishek; Yang, Hua; Mattaini, Katherine R.; Metallo, Christian M.; Fiske, Brian P.; Courtney, Kevin D.; Malstrom, Scott; Khan, Tahsin M.; Kung, Charles; Skoumbourdis, Amanda P.; Veith, Henrike; Southall, Noel; Walsh, Martin J.; Brimacombe, Kyle R.; Leister, William; Lunt, Sophia Y.; Johnson, Zachary R.; Yen, Katharine E.; Kunii, Kaiko; Davidson, Shawn M.; Christofk, Heather R.; Austin, Christopher P.; Inglese, James; Harris, Marian H.; Asara, John M.; Stephanopoulos, Gregory; Salituro, Francesco G.; Jin, Shengfang; Dang, Lenny; Auld, Douglas S.; Park, Hee-Won; Cantley, Lewis C.; Thomas, Craig J.; Vander Heiden, Matthew G.

    2012-08-26

    Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. The interaction of PKM2 with phosphotyrosine-containing proteins inhibits enzyme activity and increases the availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small-molecule PKM2 activators inhibits the growth of xenograft tumors. Structural studies reveal that small-molecule activators bind PKM2 at the subunit interaction interface, a site that is distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. This data supports the notion that small-molecule activation of PKM2 can interfere with anabolic metabolism.

  3. Activated Charcoal Suppresses Breeding of the House Dust Mite, Dermatophagoides Pteronyssinus, in Culture

    Science.gov (United States)

    Nam, Hae-Seon; Lee, Sun-Hwa; Kim, Sung-Ho; Lee, Sang-Han; Crane, Julian

    2007-01-01

    House dust mite sensitized asthmatics are advised to practice allergen avoidance. Charcoal pillows are used in Korea with unsubstantiated claims regarding their efficacy in alleviating asthma symptoms. We tested the effects of activated charcoal on breeding of house dust mites in culture. Twenty live adult house dust mites (Dermatophagoides pteronyssinus) were inoculated, 10 replicates, on culture media containing 0%, 1%, 3%, 5%, 10%, and 20% activated charcoal and incubated at 25℃ and a relative humidity of 75%. After four weeks, the mean numbers of live house dust mites were 286, 176, 46, 16, 7, and 0 for the 0%, 1%, 3%, 5%, 10%, and 20% charcoal-containing culture media, respectively. Thus, activated charcoal suppresses breeding of house dust mites and offers a new promising method for house dust mite control. PMID:17449957

  4. Treadmill exercise ameliorates symptoms of Alzheimer disease through suppressing microglial activation-induced apoptosis in rats.

    Science.gov (United States)

    Baek, Seung-Soo; Kim, Sang-Hoon

    2016-12-01

    Alzheimer disease (AD) is a most common form of dementia and eventually causes impairments of learning ability and memory function. In the present study, we investigated the effects of treadmill exercise on the symptoms of AD focusing on the microglial activation-induced apoptosis. AD was made by bilateral intracerebroventricular injection of streptozotocin. The rats in the exercise groups were made to run on a treadmill once a day for 30 min during 4 weeks. The distance and latency in the Morris water maze task and the latency in the step-down avoidance task were increased in the AD rats, in contrast, treadmill exercise shortened these parameters. The numbers of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive and caspase-3-positive cells in the hippocampal dentate gyrus were decreased in the AD rats, in contrast, treadmill exercise suppressed these numbers. Expressions of glial fibrillary acidic protein (GFAP) and cluster of differentiation molecule 11B (CD11b) in the hippocampal dentate gyrus were increased in the AD rats, in contrast, treadmill exercise suppressed GFAP and CD11b expressions. Bax expression was increased and Bcl-2 expression was decreased in the hippocampus of AD rats, in contrast, treadmill exercise decreased Bax expression and increased Bcl-2 expression. The present results demonstrated that treadmill exercise ameliorated AD-induced impairments of spatial learning ability and short-term memory through suppressing apoptosis. The antiapoptotic effect of treadmill exercise might be ascribed to the inhibitory effect of treadmill exercise on microglial activation.

  5. TGF-β suppresses β-catenin-dependent tolerogenic activation program in dendritic cells.

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    Bryan Vander Lugt

    Full Text Available The mechanisms that underlie the critical dendritic cell (DC function in maintainance of peripheral immune tolerance are incompletely understood, although the β-catenin signaling pathway is critical for this role. The molecular details by which β-catenin signaling is regulated in DCs are unknown. Mechanical disruption of murine bone marrow-derived DC (BMDC clusters activates DCs while maintaining their tolerogenic potential and this activation is associated with β-catenin signaling, providing a useful model with which to explore tolerance-associated β-catenin signaling in DCs. In this report, we demonstrate novel molecular features of the signaling events that control DC activation in response to mechanical stimulation. Non-canonical β-catenin signaling is an essential component of this tolerogenic activation and is modulated by adhesion molecules, including integrins. This unique β-catenin-dependent signaling pathway is constitutively active at low levels, suggesting that mechanical stimulation is not necessarily required for induction of this unique activation program. We additionally find that the immunomodulatory cytokine TGF-β antagonizes β-catenin in DCs, thereby selectively suppressing signaling associated with tolerogenic DC activation while having no impact on LPS-induced, β-catenin-independent immunogenic activation. These findings provide new molecular insight into the regulation of a critical signaling pathway for DC function in peripheral immune tolerance.

  6. A novel telomerase activator suppresses lung damage in a murine model of idiopathic pulmonary fibrosis.

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    Claude Jourdan Le Saux

    Full Text Available The emergence of diseases associated with telomere dysfunction, including AIDS, aplastic anemia and pulmonary fibrosis, has bolstered interest in telomerase activators. We report identification of a new small molecule activator, GRN510, with activity ex vivo and in vivo. Using a novel mouse model, we tested the potential of GRN510 to limit fibrosis induced by bleomycin in mTERT heterozygous mice. Treatment with GRN510 at 10 mg/kg/day activated telomerase 2-4 fold both in hematopoietic progenitors ex vivo and in bone marrow and lung tissue in vivo, respectively. Telomerase activation was countered by co-treatment with Imetelstat (GRN163L, a potent telomerase inhibitor. In this model of bleomycin-induced fibrosis, treatment with GRN510 suppressed the development of fibrosis and accumulation of senescent cells in the lung via a mechanism dependent upon telomerase activation. Treatment of small airway epithelial cells (SAEC or lung fibroblasts ex vivo with GRN510 revealed telomerase activating and replicative lifespan promoting effects only in the SAEC, suggesting that the mechanism accounting for the protective effects of GRN510 against induced lung fibrosis involves specific types of lung cells. Together, these results support the use of small molecule activators of telomerase in therapies to treat idiopathic pulmonary fibrosis.

  7. Technical actions, heart rate, and locomotor activity in 7v7 and 8v8 games for female youth soccer players

    DEFF Research Database (Denmark)

    Ørntoft, Christina Øyangen; Larsen, Malte Nejst; Andersen, Thomas Bull

    2016-01-01

    The purpose of this study was to evaluate technical performance, heart rate (HR), and activity profile in 7v7 and 8v8 soccer games for 9[FIGURE DASH]10-year-old girls (U11). A total of 24 female youth players participated in the study, all playing 20-min 7v7 and 8v8 games with 160 and 223 m per...

  8. Suppression of adenosine-activated chloride transport by ethanol in airway epithelia.

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    Sammeta V Raju

    Full Text Available Alcohol abuse is associated with increased lung infections. Molecular understanding of the underlying mechanisms is not complete. Airway epithelial ion transport regulates the homeostasis of airway surface liquid, essential for airway mucosal immunity and lung host defense. Here, air-liquid interface cultures of Calu-3 epithelial cells were basolaterally exposed to physiologically relevant concentrations of ethanol (0, 25, 50 and 100 mM for 24 hours and adenosine-stimulated ion transport was measured by Ussing chamber. The ethanol exposure reduced the epithelial short-circuit currents (I(SC in a dose-dependent manner. The ion currents activated by adenosine were chloride conductance mediated by cystic fibrosis transmembrane conductance regulator (CFTR, a cAMP-activated chloride channel. Alloxazine, a specific inhibitor for A(2B adenosine receptor (A(2BAR, largely abolished the adenosine-stimulated chloride transport, suggesting that A(2BAR is a major receptor responsible for regulating the chloride transport of the cells. Ethanol significantly reduced intracellular cAMP production upon adenosine stimulation. Moreover, ethanol-suppression of the chloride secretion was able to be restored by cAMP analogs or by inhibitors to block cAMP degradation. These results imply that ethanol exposure dysregulates CFTR-mediated chloride transport in airways by suppression of adenosine-A(2BAR-cAMP signaling pathway, which might contribute to alcohol-associated lung infections.

  9. Drosera rotundifolia and Drosera tokaiensis suppress the activation of HMC-1 human mast cells.

    Science.gov (United States)

    Fukushima, Kenji; Nagai, Kanji; Hoshi, Yoshikazu; Masumoto, Saeko; Mikami, Ichiho; Takahashi, Yumiko; Oike, Hideaki; Kobori, Masuko

    2009-08-17

    Several Northern Hemisphere Drosera species have been used in the therapy of respiratory tract infections as the traditional medicine Droserae Herba. To determine the anti-inflammatory effects of Drosera species and to investigate a substitute material for Droserae Herba, we examined the effect of extracts of Drosera rotundifolia, Drosera tokaiensis and Drosera spatulata on activated T cell membrane (aTc-m)-induced inflammatory gene expression in HMC-1 human mast cells. Drosera rotundifolia, Drosera spatulata and Drosera tokaiensis were collected in Japan. Herbs were extracted with 80% EtOH, and subsequently applied to OASIS HLB column. HMC-1 cells were treated with each Drosera column-adsorbed fraction for 15min, and subsequently added to aTc-m and incubated for 16h. Inflammatory gene and protein expressions were determined by DNA microarray, RT-PCR and Western blotting. Drosera rotundifolia and Drosera tokaiensis fractions, but not the Drosera spatulata fraction, suppressed inflammatory gene expression induced by aTc-m in HMC-1 cells. Drosera rotundifolia and Drosera tokaiensis suppressed activation of HMC-1 cells induced by aTc-m. Since the Drosera tokaiensis fraction was more effective than the traditionally used Drosera rotundifolia, Drosera tokaiensis is a likely substitute as a source of Droserae Herba.

  10. Dormancy of cancer cells with suppression of AKT activity contributes to survival in chronic hypoxia.

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    Hiroko Endo

    Full Text Available A hypoxic microenvironment in tumors has been recognized as a cause of malignancy or resistance to various cancer therapies. In contrast to recent progress in understanding the acute response of cancer cells to hypoxia, the characteristics of tumor cells in chronic hypoxia remain elusive. We have identified a pancreatic cancer cell line, AsPC-1, that is exceptionally able to survive for weeks under 1% oxygen conditions while most tested cancer cell lines die after only some days under these conditions. In chronic hypoxia, AsPC-1 cells entered a state of dormancy characterized by no proliferation, no death, and metabolic suppression. They reversibly switched to active status after being placed again in optimal culture conditions. ATP turnover, an indicator of energy demand, was markedly decreased and accompanied by reduced AKT phosphorylation. Forced activation of AKT resulted in increased ATP turnover and massive cell death in vitro and a decreased number of dormant cells in vivo. In contrast to most cancer cell lines, primary-cultured colorectal cancer cells easily entered the dormant status with AKT suppression under hypoxia combined with growth factor-depleted conditions. Primary colorectal cancer cells in dormancy were resistant to chemotherapy. Thus, the ability to survive in a deteriorated microenvironment by entering into dormancy under chronic hypoxia might be a common property among cancer cells. Targeting the regulatory mechanism inducing this dormant status could provide a new strategy for treating cancer.

  11. Rhodiola crenulata extract suppresses hepatic gluconeogenesis via activation of the AMPK pathway.

    Science.gov (United States)

    Lee, Shih-Yu; Lai, Feng-Yi; Shi, Li-Shian; Chou, Yu-Ching; Yen, I-Chuan; Chang, Tsu-Chung

    2015-04-15

    Rhodiola, a popular herb, has been used for treating high altitude sicknesses, depression, fatigue, and diabetes. However, the detailed mechanisms by which Rhodiola crenulata functions in the liver need further clarification. The current study was designed to examine the effects of Rhodiola crenulata root extract (RCE) on hepatic glucose production. Human hepatoma HepG2 cells were treated with RCE for 6 h. Glucose production, the expression level of p-AMPK, and the expression of key gluconeogenic genes were measured. The effects of RCE were also studied in Sprague-Dawley (SD) rats. The efficacy and underlying mechanism of RCE in the liver were examined. RCE significantly suppressed glucose production and gluconeogenic gene expression in HepG2 cells while activating the AMPK signaling pathway. Interestingly, RCE-suppressed hepatic gluconeogenesis was eliminated by an AMPK-specific inhibitor, but not by the PI3K/AKT-specific inhibitor. In addition, oral administration of RCE significantly increased phosphorylated AMPK levels and inhibited gluconeogenic gene expression in the rat liver. Furthermore, RCE treatment also decreased plasma glucose concentration in rats. We present in vitro and in vivo evidence that RCE might exert the glucose-lowering effect partly by inhibiting hepatic gluconeogenesis through activating the AMPK signaling pathway. These findings provide evidence that Rhodiola crenulata may be helpful for the management of type II diabetes. Copyright © 2015 Elsevier GmbH. All rights reserved.

  12. Secondary immunity to Legionella pneumophila and Th1 activity are suppressed by delta-9-tetrahydrocannabinol injection.

    Science.gov (United States)

    Newton, C A; Klein, T W; Friedman, H

    1994-01-01

    Resistance to infection with Legionella pneumophila is primarily dependent upon cell-mediated immunity rather than humoral immunity. Recent evidence suggests that activation of cell-mediated immunity depends on Th1 cells and activation of humoral immunity depends on Th2 cells. In this report, delta 9-tetrahydrocannabinol (THC), the major psychoactive cannabinoid of marijuana and an immunomodulator, suppressed development of secondary immunity to L. pneumophila, which correlated with a reduction in Th1 activity. BALB/c mice, infected with a primary sublethal dose of L. pneumophila, developed resistance to a larger challenge infection 3 to 4 weeks later. However, intravenous injection of THC (4 mg/kg of body weight) 1 day prior to primary infection resulted in increased mortality after the challenge infection. The level of anti-L. pneumophila antibodies in serum increased in both THC-treated and control mice; however, in the THC group IgG1 antibodies which are stimulated by Th2 cells were elevated while Th1-regulated, IgG2a antibodies were depressed. Furthermore, cultured splenocytes from THC-treated mice had less L. pneumophila-specific lymphoproliferation, indicating a deficiency in cell-mediated immunity. Normal mouse splenocytes treated in vitro with THC and pokeweed mitogen showed suppressed production of gamma interferon, a cytokine associated with Th1 cells, but increased production of interleukin 4, a cytokine produced by Th2 cells. Splenocytes from THC-treated mice, stimulated in vitro with either pokeweed mitogen or anti-CD3 antibodies, also produced less gamma interferon, indicating less Th1 activity in these mice. These results suggest that THC decreases the development of anti-L. pneumophila immunity by causing a change in the balance of Th1 and Th2 activities. PMID:8063421

  13. miR-191 suppresses angiogenesis by activation of NF-κB signaling.

    Science.gov (United States)

    Gu, Yuan; Ampofo, Emmanuel; Menger, Michael D; Laschke, Matthias W

    2017-08-01

    MicroRNAs (miRNAs) are powerful regulators of diverse biologic processes. However, the function of most miRNAs in angiogenesis remains elusive. In this study, we identified miR-191-5p (miR-191) as a potent inhibitor of blood vessel development. Transfection of human dermal microvascular endothelial cells with miR-191 mimic (miR-191m) inhibited their proliferation, migration, and tube formation. Moreover, vascular sprouting of miR-191m-transfected mouse aortic rings was significantly reduced when compared with controls. Transfection with miR-191 inhibitor (miR-191i) induced proangiogenic effects. The anti- and proangiogenic activities of miR-191m and -191i were further demonstrated in vivo Additional molecular biologic analyses revealed that miR-191m activates NF-κB signaling by up-regulating the mRNA expression of p65. miR-191 also increased the mRNA levels of the antiangiogenic factors p21 and tissue inhibitor of metalloproteinase-1 and reduced the expression of the proangiogenic factors eNOS and matrix metalloproteinase-1 and -9. Blockade of NF-κB activation with Bay 11-7082 reversed the antiangiogenic effects of miR-191m. These findings indicate that miR-191 effectively suppresses angiogenesis by activation of the NF-κB signaling pathway.-Gu, Y., Ampofo, E., Menger, M. D., Laschke, M. W. miR-191 suppresses angiogenesis by activation of NF-κB signaling. © FASEB.

  14. The influence of age on learning a locomotor task.

    Science.gov (United States)

    van Hedel, H J A; Dietz, V

    2004-09-01

    Knowledge about locomotor task performance and learning in the elderly is important in optimizing rehabilitation strategies. The aim of this study was to evaluate differences between young and elderly subjects in the acquisition and performance of a precision locomotor task, with full and restricted vision. The subjects walked on a treadmill and had to step as low as possible over an obstacle, without touching it. They received acoustic warning and feedback signals, indicating obstacle appearance and foot clearance, respectively. Full vision was provided during the first two runs and became restricted during the third run. The number of obstacle hits and adaptations in foot clearance, leg muscle activity, range of motion of leg joints and swing phase duration were assessed. With vision, the performance improved in both groups. Restricted vision reduced the task accuracy in both the young and the elderly. However, only the young subjects regained optimal foot clearance with practice. Elderly subjects rely more on visual control when acquiring and performing a precision locomotor task. We suggest that this is due to an impaired function of proprioceptive feedback mechanisms, which can replace visual information in young subjects. In the elderly, therapeutical attention should be directed towards optimizing the use of the remaining proprioceptive inputs.

  15. Knockdown of Pokemon protein expression inhibits hepatocellular carcinoma cell proliferation by suppression of AKT activity.

    Science.gov (United States)

    Zhu, Xiaosan; Dai, Yichen; Chen, Zhangxin; Xie, Junpei; Zeng, Wei; Lin, Yuanyuan

    2013-01-01

    Overexpression of Pokemon, which is an erythroid myeloid ontogenic factor protein, occurs in different cancers, including hepatocellular carcinoma (HCC). Pokemon is also reported to have an oncogenic activity in various human cancers. This study investigated the effect of Pokemon knockdown on the regulation of HCC growth. POK shRNA suppressed the expression of Pokemon protein in HepG2 cells compared to the negative control vector-transfected HCC cells. Pokemon knockdown also reduced HCC cell viability and enhanced cisplatin-induced apoptosis in HCC cells. AKT activation and the expression of various cell cycle-related genes were inhibited following Pokemon knockdown. These data demonstrate that Pokemon may play a role in HCC progression, suggesting that inhibition of Pokemon expression using Pokemon shRNA should be further evaluated as a novel target for the control of HCC.

  16. A maternal high-fat, high-sucrose diet has sex-specific effects on fetal glucocorticoids with little consequence for offspring metabolism and voluntary locomotor activity in mice.

    Science.gov (United States)

    Chin, Eunice H; Schmidt, Kim L; Martel, Kaitlyn M; Wong, Chi Kin; Hamden, Jordan E; Gibson, William T; Soma, Kiran K; Christians, Julian K

    2017-01-01

    Maternal overnutrition and obesity during pregnancy can have long-term effects on offspring physiology and behaviour. These developmental programming effects may be mediated by fetal exposure to glucocorticoids, which is regulated in part by placental 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 and 2. We tested whether a maternal high-fat, high-sucrose diet would alter expression of placental 11β-HSD1 and 2, thereby increasing fetal exposure to maternal glucocorticoids, with downstream effects on offspring physiology and behaviour. C57BL/6J mice were fed a high-fat, high-sucrose (HFHS) diet or a nutrient-matched low-fat, no-sucrose control diet prior to and during pregnancy and lactation. At day 17 of gestation, HFHS dams had ~20% lower circulating corticosterone levels than controls. Furthermore, there was a significant interaction between maternal diet and fetal sex for circulating corticosterone levels in the fetuses, whereby HFHS males tended to have higher corticosterone than control males, with no effect in female fetuses. However, placental 11β-HSD1 or 11β-HSD2 expression did not differ between diets or show an interaction between diet and sex. To assess potential long-term consequences of this sex-specific effect on fetal corticosterone, we studied locomotor activity and metabolic traits in adult offspring. Despite a sex-specific effect of maternal diet on fetal glucocorticoids, there was little evidence of sex-specific effects on offspring physiology or behaviour, although HFHS offspring of both sexes had higher circulating corticosterone at 9 weeks of age. Our results suggest the existence of as yet unknown mechanisms that mitigate the effects of altered glucocorticoid exposure early in development, making offspring resilient to the potentially negative effects of a HFHS maternal diet.

  17. A maternal high-fat, high-sucrose diet has sex-specific effects on fetal glucocorticoids with little consequence for offspring metabolism and voluntary locomotor activity in mice.

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    Eunice H Chin

    Full Text Available Maternal overnutrition and obesity during pregnancy can have long-term effects on offspring physiology and behaviour. These developmental programming effects may be mediated by fetal exposure to glucocorticoids, which is regulated in part by placental 11β-hydroxysteroid dehydrogenase (11β-HSD type 1 and 2. We tested whether a maternal high-fat, high-sucrose diet would alter expression of placental 11β-HSD1 and 2, thereby increasing fetal exposure to maternal glucocorticoids, with downstream effects on offspring physiology and behaviour. C57BL/6J mice were fed a high-fat, high-sucrose (HFHS diet or a nutrient-matched low-fat, no-sucrose control diet prior to and during pregnancy and lactation. At day 17 of gestation, HFHS dams had ~20% lower circulating corticosterone levels than controls. Furthermore, there was a significant interaction between maternal diet and fetal sex for circulating corticosterone levels in the fetuses, whereby HFHS males tended to have higher corticosterone than control males, with no effect in female fetuses. However, placental 11β-HSD1 or 11β-HSD2 expression did not differ between diets or show an interaction between diet and sex. To assess potential long-term consequences of this sex-specific effect on fetal corticosterone, we studied locomotor activity and metabolic traits in adult offspring. Despite a sex-specific effect of maternal diet on fetal glucocorticoids, there was little evidence of sex-specific effects on offspring physiology or behaviour, although HFHS offspring of both sexes had higher circulating corticosterone at 9 weeks of age. Our results suggest the existence of as yet unknown mechanisms that mitigate the effects of altered glucocorticoid exposure early in development, making offspring resilient to the potentially negative effects of a HFHS maternal diet.

  18. Dihydromyricetin Protects against Bone Loss in Ovariectomized Mice by Suppressing Osteoclast Activity

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    Libo Zhao

    2017-12-01

    Full Text Available Dihydromyricetin (DMY, the main flavonoid component of Ampelopsis grossedentata, possesses pharmacological activities useful for treatment of diseases associated with inflammation and oxidative damage. Because osteoclasts are often involved in chronic low-grade systemic inflammation and oxidative damage, we hypothesized that DMY may be an effective treatment for osteoclast-related diseases. The effects of DMY on osteoclast formation and activity were examined in vitro. Female C57BL/6 mice were ovariectomized to mimic menopause-induced bone loss and treated with DMY, and femur samples were subjected to bone structure and histological analysis, serum biochemical indicators were also measured. DMY suppressed the activation of nuclear factor-κB, c-Fos and mitogen-activated protein kinase, and prevented production of reactive oxygen species. DMY decreased expression of osteoclast-specific genes, including Trap, Mmp-9, Cathepsin K, C-Fos, Nfatc1, and Rank. In addition, DMY prevented bone loss and decreased serum levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6, and with a decrease in the ratio between receptor activator of nuclear factor-κB (RANK ligand (RANKL and osteoprotegerin (OPG in vivo. These findings demonstrate that DMY attenuates bone loss and inhibits osteoclast formation and activity through modulation of multiple pathways both upstream and downstream of RANKL signaling. DMY may thus be a useful option for treatment of osteoclast-related diseases such as rheumatoid arthritis and osteoporosis.

  19. Reverse feeding suppresses the activity of the GH axis in rats and induces a preobesogenic state.

    Science.gov (United States)

    Glad, Camilla A-M; Kitchen, Edward E J; Russ, Gemma C; Harris, Sophie M; Davies, Jeffrey S; Gevers, Evelien F; Gabrielsson, Britt G; Wells, Timothy

    2011-03-01

    Reversed feeding (RF) is known to disrupt hormone rhythmicity and metabolism. Although these effects may be mediated in part by phase inversion of glucocorticoid secretion, the precise mechanism is incompletely characterized. In this study, we demonstrate that acute nocturnal food deprivation in male rats suppressed the amplitude of spontaneous GH secretion during the dark phase by 62% (P inversion of core clock gene expression in liver, abdominal white adipose tissue (WAT) and skeletal muscle, without affecting their expression patterns in the suprachiasmatic nucleus. In addition, RF resulted in phase inversion of hepatic peroxisome proliferator-activated receptor γ2 mRNA expression, a 3- to 5-fold elevation in fatty acid synthase mRNA in WAT in both light- and dark-phase samples (P < 0.01) and an elevation in muscle uncoupling protein 3 mRNA expression at the beginning of the light phase (P < 0.01). Consumption of a high-fat diet increased inguinal (by 36%; P < 0.05) and retroperitoneal WAT weight (by 72%; P < 0.01) only in RF-maintained rats, doubling the efficiency of lipid accumulation (P < 0.05). Thus, RF not only desynchronizes central and peripheral circadian clocks, and suppresses nocturnal GH secretion, but induces a preobesogenic state.

  20. The Ustilago maydis effector Pep1 suppresses plant immunity by inhibition of host peroxidase activity.

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    Christoph Hemetsberger

    Full Text Available The corn smut Ustilago maydis establishes a biotrophic interaction with its host plant maize. This interaction requires efficient suppression of plant immune responses, which is attributed to secreted effector proteins. Previously we identified Pep1 (Protein essential during penetration-1 as a secreted effector with an essential role for U. maydis virulence. pep1 deletion mutants induce strong defense responses leading to an early block in pathogenic development of the fungus. Using cytological and functional assays we show that Pep1 functions as an inhibitor of plant peroxidases. At sites of Δpep1 mutant penetrations, H₂O₂ strongly accumulated in the cell walls, coinciding with a transcriptional induction of the secreted maize peroxidase POX12. Pep1 protein effectively inhibited the peroxidase driven oxidative burst and thereby suppresses the early immune responses of maize. Moreover, Pep1 directly inhibits peroxidases in vitro in a concentration-dependent manner. Using fluorescence complementation assays, we observed a direct interaction of Pep1 and the maize peroxidase POX12 in vivo. Functional relevance of this interaction was demonstrated by partial complementation of the Δpep1 mutant defect by virus induced gene silencing of maize POX12. We conclude that Pep1 acts as a potent suppressor of early plant defenses by inhibition of peroxidase activity. Thus, it represents a novel strategy for establishing a biotrophic interaction.

  1. H-reflex suppression and autonomic activation during lucid REM sleep: a case study.

    Science.gov (United States)

    Brylowski, A; Levitan, L; LaBerge, S

    1989-08-01

    A single subject, a proficient lucid dreamer experienced with signaling the onset of lucidity (reflective consciousness of dreaming) by means of voluntary eye movements, spent 4 nonconsecutive nights in the sleep laboratory. The subject reported becoming lucid and signaling in 8 of the 18 rapid-eye movement (REM) periods recorded. Ten lucid dream reports were verified by polygraphic examination of signals, providing a total of 12.5 min of signal-verified lucid REM. H-Reflex amplitude was recorded every 5 s, along with continuous recording of electroencephalogram, electrooculogram, electromyogram, electrocardiogram, finger pulse, and respiration. Significant findings included greater mean H-reflex suppression during lucid REM sleep than during nonlucid REM and correlations of H-reflex suppression with increased eye movement density, heart rate, and respiration rate. These results support previous studies reporting that lucid REM is not, as might be supposed, a state closer to awakening than ordinary, or nonlucid, REM; rather, lucid dreaming occurs during unequivocal REM sleep and is characteristically associated with phasic REM activation.

  2. Aryl Hydrocarbon Receptor Activation Suppresses EBF1 and PAX5 and Impairs Human B Lymphopoiesis.

    Science.gov (United States)

    Li, Jinpeng; Bhattacharya, Sudin; Zhou, Jiajun; Phadnis-Moghe, Ashwini S; Crawford, Robert B; Kaminski, Norbert E

    2017-11-15

    Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates biological responses to endogenous and environmental chemical cues. Increasing evidence shows that the AHR plays physiological roles in regulating development, homeostasis, and function of a variety of cell lineages in the immune system. However, the role of AHR in human B cell development has not been investigated. Toward this end, an in vitro feeder-free human B cell developmental model system was employed using human cord blood CD34 + hematopoietic stem/progenitor cells. Using this model, we found that AHR activation by the high-affinity ligand 2,3,7,8-tetrachlorodibenzo- p -dioxin significantly suppressed the generation of early B cells and pro-B cells from hematopoietic stem/progenitor cells, indicating the impairment of B cell lineage specification and commitment. Addition of an AHR antagonist reversed 2,3,7,8-tetrachlorodibenzo- p -dioxin-elicited suppression of early B and pro-B cells, suggesting a role of AHR in regulating B lymphopoiesis. Gene expression analysis revealed a significant decrease in the messenger RNA level of early B cell factor 1 (EBF1) and paired box 5, two critical transcription factors directing B cell lineage specification and commitment. Additionally, binding of the ligand-activated AHR to the putative dioxin response elements in the EBF1 promoter was demonstrated by EMSAs and chromatin immunoprecipitation analysis, suggesting transcriptional regulation of EBF1 by AHR. Taken together, this study demonstrates a role for the AHR in regulating human B cell development, and it suggests that transcriptional alterations of EBF1 by the AHR are involved in the underlying mechanism. Copyright © 2017 by The American Association of Immunologists, Inc.

  3. Sodium salicylate suppresses GABAergic inhibitory activity in neurons of rodent dorsal raphe nucleus.

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    Yan Jin

    Full Text Available Sodium salicylate (NaSal, a tinnitus inducing agent, can activate serotonergic (5-HTergic neurons in the dorsal raphe nucleus (DRN and can increase serotonin (5-HT level in the inferior colliculus and the auditory cortex in rodents. To explore the underlying neural mechanisms, we first examined effects of NaSal on neuronal intrinsic properties and the inhibitory synaptic transmissions in DRN slices of rats by using whole-cell patch-clamp technique. We found that NaSal hyperpolarized the resting membrane potential, decreased the input resistance, and suppressed spontaneous and current-evoked firing in GABAergic neurons, but not in 5-HTergic neurons. In addition, NaSal reduced GABAergic spontaneous and miniature inhibitory postsynaptic currents in 5-HTergic neurons. We next examined whether the observed depression of GABAergic activity would cause an increase in the excitability of 5-HTergic neurons using optogenetic technique in DRN slices of the transgenic mouse with channelrhodopsin-2 expressed in GABAergic neurons. When the GABAergic inhibition was enhanced by optical stimulation to GABAergic neurons in mouse DRN, NaSal significantly depolarized the resting membrane potential, increased the input resistance and increased current-evoked firing of 5-HTergic neurons. However, NaSal would fail to increase the excitability of 5-HTergic neurons when the GABAergic synaptic transmission was blocked by picrotoxin, a GABA receptor antagonist. Our results indicate that NaSal suppresses the GABAergic activities to raise the excitability of local 5-HTergic neural circuits in the DRN, which may contribute to the elevated 5-HT level by NaSal in the brain.

  4. Sodium salicylate suppresses GABAergic inhibitory activity in neurons of rodent dorsal raphe nucleus.

    Science.gov (United States)

    Jin, Yan; Luo, Bin; Su, Yan-Yan; Wang, Xin-Xing; Chen, Liang; Wang, Ming; Wang, Wei-Wen; Chen, Lin

    2015-01-01

    Sodium salicylate (NaSal), a tinnitus inducing agent, can activate serotonergic (5-HTergic) neurons in the dorsal raphe nucleus (DRN) and can increase serotonin (5-HT) level in the inferior colliculus and the auditory cortex in rodents. To explore the underlying neural mechanisms, we first examined effects of NaSal on neuronal intrinsic properties and the inhibitory synaptic transmissions in DRN slices of rats by using whole-cell patch-clamp technique. We found that NaSal hyperpolarized the resting membrane potential, decreased the input resistance, and suppressed spontaneous and current-evoked firing in GABAergic neurons, but not in 5-HTergic neurons. In addition, NaSal reduced GABAergic spontaneous and miniature inhibitory postsynaptic currents in 5-HTergic neurons. We next examined whether the observed depression of GABAergic activity would cause an increase in the excitability of 5-HTergic neurons using optogenetic technique in DRN slices of the transgenic mouse with channelrhodopsin-2 expressed in GABAergic neurons. When the GABAergic inhibition was enhanced by optical stimulation to GABAergic neurons in mouse DRN, NaSal significantly depolarized the resting membrane potential, increased the input resistance and increased current-evoked firing of 5-HTergic neurons. However, NaSal would fail to increase the excitability of 5-HTergic neurons when the GABAergic synaptic transmission was blocked by picrotoxin, a GABA receptor antagonist. Our results indicate that NaSal suppresses the GABAergic activities to raise the excitability of local 5-HTergic neural circuits in the DRN, which may contribute to the elevated 5-HT level by NaSal in the brain.

  5. Targeted p53 activation by saRNA suppresses human bladder cancer cells growth and metastasis.

    Science.gov (United States)

    Wang, Chenghe; Ge, Qiangqiang; Zhang, Qingsong; Chen, Zhong; Hu, Jia; Li, Fan; Ye, Zhangqun

    2016-03-25

    Previous study showed that dsP53-285 has the capacity to induce tumor suppressor gene p53 expression by targeting promoter in non-human primates' cells. And it is well known that TP53 gene is frequently mutant or inactivated in human bladder cancer. Hereby, whether this small RNA can activate the expression of wild-type p53 and inhibit human bladder cancer cells remains to be elucidated. Oligonucleotide and lentivirus were used to overexpress dsP53-285 and dsControl. Real-time PCR and western blot were used to detect genes' mRNA and protein expression, respectively. Cell proliferation assay, colony formation, flow cytometry, transwell assay and wound healing assay were performed to determine the effects on bladder cancer cells proliferation and migration/invasion in vitro. Animal models were carried out to analyze the effects on cells growth and metastasis in vivo. Transfection of dsP53-285 into human bladder cancer cell lines T24 and EJ readily activate wild-type p53 expression by targeting promoter. Moreover, dsP53-285 exhibited robust capacity to inhibit cells proliferation and colony formation, induce cells G0/G1 arrest, suppress migration and invasion. Besides, the Cyclin-CDK genes (Cyclin D1 and CDK4/6) were down-regulated and the EMT-associated genes (E-cadherin, β-catenin, ZEB1 and Vimentin) were also expressed inversely after dsP53-285 treatment. In addition, dsP53-285 could also significantly suppress the growth of bladder cancer xenografts and metastasis in nude mice. Most importantly, the anti-tumor effects mediated by dsP53-285 were mainly achieved by manipulating wild-type p53 expression. Our findings indicate that the dsP53-285 can upregulate wild-type p53 expression in human bladder cancer cells through RNA activation, and suppresses cells proliferation and metastasis in vitro and in vivo.

  6. Simvastatin suppresses dexamethasone-induced secretion of plasminogen activator inhibitor-1 in human bone marrow adipocytes

    Directory of Open Access Journals (Sweden)

    Baba Hideo

    2011-04-01

    Full Text Available Abstract Background Osteonecrosis of the femoral head is a common complication of high-dose glucocorticoid treatment. Intravascular thrombosis is thought to be associated with the ischemic state of the femoral head. Plasminogen activator inhibitor-1 (PAI-1 is an adipokine, which are physiologically active substances secreted from visceral and subcutaneous adipocytes. PAI-1 suppresses fibrinolysis by binding tissue-type plasminogen activator. Several reports have described the relationship between PAI-1 and steroid-induced osteonecrosis of the femoral head, and the preventive effects of lipid-lowering agents (statins against steroid-induced osteonecrosis of the femoral head. We previously reported that adipokines and dexamethasone induced PAI-1 secretion from bone marrow adipocytes. The purpose of the present study is to examine the effects of simvastatin on PAI-1 secretion from human bone marrow adipocytes in vitro. Methods Primary bone marrow adipocytes were extracted from collagenase-treated bone marrow fluid obtained from the femoral necks of 40 patients (6 men, 34 women; age range, 52-81 years undergoing hip joint replacement surgery. After suspended culture with or without dexamethasone or simvastatin, PAI-1 mRNA expression was assessed by real-time RT-PCR. Total PAI-1 protein secretion in culture medium was assessed by enzyme-linked immunosorbent assay. Results PAI-1 mRNA expression was up-regulated by 388% (P = 0.002 with dexamethasone, and down-regulated by 45% (P = 0.002 with simvastatin, as compared to control levels. Dexamethasone increased total PAI-1 secretion by 166% (P = 0.001 and simvastatin decreased total PAI-1 secretion by 64% (P = 0.002. No significant changes were observed in adiponectin mRNA expression and secretion by dexamethasone and simvastatin, while pre-treatment with simvastatin reversed dexamethasone induced PAI-1 secretion by 89%, as compared to control levels. Conclusion The present study confirmed the suppressive

  7. Passion flower extract antagonizes the expression of nicotine locomotor sensitization in rats.

    Science.gov (United States)

    Breivogel, Chris; Jamerson, Brenda

    2012-10-01

    Nicotine, a bioactive component of tobacco, is highly addictive. Numerous therapies have been developed or are currently under investigation for smoking cessation, and all have met with limited success and/or side effects, indicating the need for additional therapies. This study examines the ability of a commerically-available aqueous extract of Passiflora incarnata Linn. (Passifloraceae) to ameliorate the signs of nicotine sensitization using a rat model. Rats were administered 0.4 mg/kg nicotine or vehicle once a day for four consecutive days. Nicotine adminstration produces sensitization of locomotor activity, a phenomenon implicated in the development of nicotine dependence. On the fifth day, locomotor activity of the subjects was monitored as rats from each treatment group were administered 800 mg/kg of Passiflora incarnata extract (or its vehicle) followed by a challenge dose of 0.4 mg/kg nicotine. When given to rats sensitized to nicotine for 4 days, the challenge dose of nicotine increased locomotor activity by more than 2-fold over activity following nicotine challenge in rats treated with vehicle during the sensitization phase. The difference was significant from 15-40 min after nicotine administration. Rats sensitized to nicotine then treated with Passiflora incarnata extract prior to the nicotine challenge exhibited a level of locomotor activity the same as the vehicle-treated controls. Passiflora incarnata extract did antagonize the expression of nicotine locomotor sensitization. Passiflora incarnata extract should be examined in future studies to evaluate its potential for treating nicotine addiction in humans.

  8. Footwear and locomotor skill performance in preschoolers.

    Science.gov (United States)

    Robinson, Leah E; Rudisill, Mary E; Weimar, Wendi H; Breslin, Casey M; Shroyer, Justin F; Morera, Maria

    2011-10-01

    The effect of footwear on locomotor skill performance was examined. 12 children (4 boys, 8 girls; M age = 56.3 mo., SD = 3.3) served as participants. Participants were randomly assigned to perform the locomotor subscale of Ulrich's Test of Gross Motor Development in two shoe conditions (Condition 1: Stride Rite athletic shoes, and Condition 2: flip flop sandals). Children scored significantly higher when wearing athletic shoes than flip-flop sandals. This finding is relevant for motor performance and safety in physical education and movement programs.

  9. Control of immune ligands by members of a cytomegalovirus gene expansion suppresses natural killer cell activation.

    Science.gov (United States)

    Fielding, Ceri A; Weekes, Michael P; Nobre, Luis V; Ruckova, Eva; Wilkie, Gavin S; Paulo, Joao A; Chang, Chiwen; Suárez, Nicolás M; Davies, James A; Antrobus, Robin; Stanton, Richard J; Aicheler, Rebecca J; Nichols, Hester; Vojtesek, Borek; Trowsdale, John; Davison, Andrew J; Gygi, Steven P; Tomasec, Peter; Lehner, Paul J; Wilkinson, Gavin W G

    2017-02-10

    The human cytomegalovirus (HCMV) US12 family consists of ten sequentially arranged genes (US12-21) with poorly characterized function. We now identify novel natural killer (NK) cell evasion functions for four members: US12, US14, US18 and US20. Using a systematic multiplexed proteomics approach to quantify ~1300 cell surface and ~7200 whole cell proteins, we demonstrate that the US12 family selectively targets plasma membrane proteins and plays key roles in regulating NK ligands, adhesion molecules and cytokine receptors. US18 and US20 work in concert to suppress cell surface expression of the critical NKp30 ligand B7-H6 thus inhibiting NK cell activation. The US12 family is therefore identified as a major new hub of immune regulation.

  10. Inverse agonistic activity of antihistamines and suppression of histamine H1 receptor gene expression.

    Science.gov (United States)

    Mizuguchi, Hiroyuki; Ono, Shohei; Hattori, Masashi; Fukui, Hiroyuki

    2012-01-01

    Histamine H(1) receptor (H1R) expression influences the severity of allergy symptoms. We examined the effect of inverse agonists on H1R gene expression. Two inverse agonists (carebastine and mepyramine), but not the neutral antagonist oxatomide, decreased inositol phosphate accumulation. The inverse agonists also decreased H1R gene expression and down-regulated H1R mRNA below basal expression, while basal H1R mRNA expression was maintained after oxatomide treatment. These results suggest that inverse agonists more potently alleviate allergy symptoms by not only inhibiting stimulus-induced up-regulation of H1R gene expression but also by suppressing basal histamine signaling through their inverse agonistic activity.

  11. Sodium azide suppresses LPS-induced expression MCP-1 through regulating IκBζ and STAT1 activities in macrophages.

    Science.gov (United States)

    Park, Cho-Yi; Heo, Jae-Nyoung; Suk, Kyoungho; Lee, Won-Ha

    2017-05-01

    Sodium azide (NaN 3 ) is a chemical compound with multiple toxic effects on vascular and neuronal systems, causing hypotension and neurotoxicity, respectively. In order to test its effects on the immune system, human and mouse macrophage-like cell lines were treated with nontoxic doses of NaN 3 and the changes in LPS-induced inflammatory activation was measured. Interestingly, the LPS-induced expression of monocyte chemoattractant protein (MCP)-1 was suppressed by NaN 3 without affecting the expression of IL-8 and TNF-α. Further analysis of cellular signaling mediators involved in the expression of these cytokines revealed that NaN 3 suppressed the LPS-induced activation of signal transducers and activator of transcription (STAT)1 and inhibitor of κB (IκB) ς, which are involved in the LPS-induced expression of MCP-1, while the LPS-induced activation of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) was not affected. The LPS-induced expression of MCP-2 and CXCL10, which are also regulated by STAT1, was suppressed by NaN 3 . Similarly, the LPS-induced expression of IL-6, which is regulated by IκBζ, was suppressed by NaN 3 . These results demonstrate that NaN 3 selectively suppresses the LPS-induced expression of pro-inflammatory mediators through the suppression of STAT1 and IκBζ activation. These new findings about the activity of NaN 3 may contribute to the development of specific regulators of macrophage activity during acute and chronic inflammation. Copyright © 2017. Published by Elsevier Inc.

  12. Novel direct AMPK activator suppresses non-small cell lung cancer through inhibition of lipid metabolism

    Science.gov (United States)

    Chen, Xi; Xie, Chun; Fan, Xing-Xing; Jiang, Ze-Bo; Wong, Vincent Kam-Wai; Xu, Jia-Hui; Yao, Xiao-Jun; Liu, Liang; Leung, Elaine Lai-Han

    2017-01-01

    Drug resistance is becoming an obstacle in anti-cancer therapies. For target-based therapy of lung cancer, gefitinib, as the first generation of tyrosine kinase inhibitors (TKIs), demonstrated good initial response to the non-small cell lung cancer (NSCLC) patients whom harbors epidermal growth factor receptor (EGFR) mutation. However, within one year, additional EGFR mutation occurred, leading to eventual gefitinib-resistance. Therefore, it is urgently to discover novel effective small molecule inhibitors for those patients. Abnormal energy metabolism is accepted as new cancer hallmark. Recently, a metabolism rate-limiting enzyme 5’-adenosine menophosphate-activated protein kinase (AMPK) has become a promising anti-cancer target. In this study, we have identified a novel direct AMPK agonist, D561-0775 from a compound library by using molecular docking screening technique. We demonstrated that D561-0775 exhibited significant inhibitory effect on gefitinib-resistant NSCLC cell lines but less cytotoxicity on normal cells. Furthermore, D561-0775 demonstrated a remarkable in vitro AMPK enzyme activation effect. Taken together, D561-0775 showed potential anti-cancer activity via inducing apoptosis, cell cycle arrest, suppressing glycolysis and cholesterol synthesis after activation of AMPK in gefitinib-resistant H1975 cells. D561-0775 has provided a new chemical structure that could be developed as cancer drug for gefitinib-resistant NSCLC patients through inhibition lipid metabolism by directly targeting at AMPK directly. PMID:29221189

  13. Chicoric acid suppresses BAFF expression in B lymphocytes by inhibiting NF-κB activity.

    Science.gov (United States)

    Chen, Lingxi; Huang, Gang; Gao, Min; Shen, Xiaodong; Gong, Wei; Xu, Zhizhen; Zeng, Yijun; He, Fengtian

    2017-03-01

    B cell activating factor belonging to the TNF family (BAFF) plays a critical role in the pathogenesis of autoimmune diseases. The inhibition of BAFF expression is an emerging therapeutic approach for these disorders. Chicoric acid (CA), a bioactive phytochemical found in several widely used traditional medicinal plants, has significant anti-inflammatory activity and anti-arthritic effects. However, the role of CA in modulation of BAFF expression remains unknown. In this study, we demonstrated that CA reduced BAFF expression in human B lymphocyte cell lines and decreased the DNA-binding activity of nuclear factor-κB (NF-κB) in the BAFF promoter region. Furthermore, CA inhibited both the nuclear translocation of p65 (the subunit of NF-κB) and the phosphorylation of IκBα (inhibitor of NF-κB). These results suggest that CA suppresses BAFF expression by inhibiting NF-κB activity, and CA may serve as a novel therapeutic agent to down-regulate excessive BAFF expression in autoimmune diseases. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Progesterone receptor antagonist CDB-4124 increases depression-like behavior in mice without affecting locomotor ability

    Science.gov (United States)

    Beckley, Ethan H.; Scibelli, Angela C.; Finn, Deborah A.

    2010-01-01

    Progesterone withdrawal has been proposed as an underlying factor in premenstrual syndrome and postpartum depression. Progesterone withdrawal induces forced swim test (FST) immobility in mice, a depression-like behavior, but the contribution of specific receptors to this effect is unclear. The role of progesterone’s GABAA receptor-modulating metabolite allopregnanolone in depression- and anxiety-related behaviors has been extensively documented, but little attention has been paid to the role of progesterone receptors. We administered the classic progesterone receptor antagonist mifepristone (RU-38486) and the specific progesterone receptor antagonist CDB-4124 to mice that had been primed with progesterone for five days, and found that both compounds induced FST immobility reliably, robustly, and in a dose-dependent fashion. Although CDB-4124 increased FST immobility, it did not suppress initial activity in a locomotor test. These findings suggest that decreased progesterone receptor activity contributes to depression-like behavior in mice, consistent with the hypothesis that progesterone withdrawal may contribute to the symptoms of premenstrual syndrome or postpartum depression. PMID:21163582

  15. Locomotor training with body weight support in SCI : EMG improvement is more optimally expressed at a low testing speed

    NARCIS (Netherlands)

    Meyns, P.; Van de Crommert, H. W. A. A.; Rijken, H.; van Kuppevelt, D. H. J. M.; Duysens, J.

    2014-01-01

    Study design: Case series. Objectives: To determine the optimal testing speed at which the recovery of the EMG (electromyographic) activity should be assessed during and after body weight supported (BWS) locomotor training. Setting: Tertiary hospital, Sint Maartenskliniek, Nijmegen, The Netherlands.

  16. Inhibiting aerobic glycolysis suppresses renal interstitial fibroblast activation and renal fibrosis.

    Science.gov (United States)

    Ding, Hao; Jiang, Lei; Xu, Jing; Bai, Feng; Zhou, Yang; Yuan, Qi; Luo, Jing; Zen, Ke; Yang, Junwei

    2017-09-01

    Chronic kidney diseases generally lead to renal fibrosis. Despite great progress having been made in identifying molecular mediators of fibrosis, the mechanism that governs renal fibrosis remains unclear, and so far no effective therapeutic antifibrosis strategy is available. Here we demonstrated that a switch of metabolism from oxidative phosphorylation to aerobic glycolysis (Warburg effect) in renal fibroblasts was the primary feature of fibroblast activation during renal fibrosis and that suppressing renal fibroblast aerobic glycolysis could significantly reduce renal fibrosis. Both gene and protein assay showed that the expression of glycolysis enzymes was upregulated in mouse kidneys with unilateral ureter obstruction (UUO) surgery or in transforming growth factor-β1 (TGF-β1)-treated renal interstitial fibroblasts. Aerobic glycolysis flux, indicated by glucose uptake and lactate production, was increased in mouse kidney with UUO nephropathy or TGF-β1-treated renal interstitial fibroblasts and positively correlated with fibrosis process. In line with this, we found that increasing aerobic glycolysis can remarkably induce myofibroblast activation while aerobic glycolysis inhibitors shikonin and 2-deoxyglucose attenuate UUO-induced mouse renal fibrosis and TGF-β1-stimulated myofibroblast activation. Furthermore, mechanistic study indicated that shikonin inhibits renal aerobic glycolysis via reducing phosphorylation of pyruvate kinase type M2, a rate-limiting glycolytic enzyme associated with cell reliance on aerobic glycolysis. In conclusion, our findings demonstrate the critical role of aerobic glycolysis in renal fibrosis and support treatment with aerobic glycolysis inhibitors as a potential antifibrotic strategy. Copyright © 2017 the American Physiological Society.

  17. Profiling of Sox4-dependent transcriptome in skin links tumour suppression and adult stem cell activation

    Directory of Open Access Journals (Sweden)

    Miguel Foronda

    2015-12-01

    Full Text Available Adult stem cells (ASCs reside in specific niches in a quiescent state in adult mammals. Upon specific cues they become activated and respond by self-renewing and differentiating into newly generated specialised cells that ensure appropriate tissue fitness. ASC quiescence also serves as a tumour suppression mechanism by hampering cellular transformation and expansion (White AC et al., 2014. Some genes restricted to early embryonic development and adult stem cell niches are often potent modulators of stem cell quiescence, and derailed expression of these is commonly associated to cancer (Vervoort SJ et al., 2013. Among them, it has been shown that recommissioned Sox4 expression facilitates proliferation, survival and migration of malignant cells. By generating a conditional Knockout mouse model in stratified epithelia (Sox4cKO mice, we demonstrated a delayed plucking-induced Anagen in the absence of Sox4. Skin global transcriptome analysis revealed a prominent defect in the induction of transcriptional networks that control hair follicle stem cell (HFSC activation such as those regulated by Wnt/Ctnnb1, Shh, Myc or Sox9, cell cycle and DNA damage response-associated pathways. Besides, Sox4cKO mice are resistant to skin carcinogenesis, thus linking Sox4 to both normal and pathological HFSC activation (Foronda M et al., 2014. Here we provide additional details on the analysis of Sox4-regulated transcriptome in Telogen and Anagen skin. The raw and processed microarray data is deposited in GEO under GSE58155.

  18. Locomotor Experience Affects Self and Emotion

    Science.gov (United States)

    Uchiyama, Ichiro; Anderson, David I.; Campos, Joseph J.; Witherington, David; Frankel, Carl B.; Lejeune, Laure; Barbu-Roth, Marianne

    2008-01-01

    Two studies investigated the role of locomotor experience on visual proprioception in 8-month-old infants. "Visual proprioception" refers to the sense of self-motion induced in a static person by patterns of optic flow. A moving room apparatus permitted displacement of an entire enclosure (except for the floor) or the side walls and…

  19. Constitutively Active Parathyroid Hormone Receptor Signaling in Cells in Osteoblastic Lineage Suppresses Mechanical Unloading-induced Bone Resorption*

    Science.gov (United States)

    Ono, Noriaki; Nakashima, Kazuhisa; Schipani, Ernestina; Hayata, Tadayoshi; Ezura, Yoichi; Soma, Kunimichi; Kronenberg, Henry M.; Noda, Masaki

    2013-01-01

    Multiple signaling pathways participate in the regulation of bone remodeling, and pathological negative balance in the regulation results in osteoporosis. However, interactions of signaling pathways that act comprehensively in concert to maintain bone mass are not fully understood. We investigated roles of parathyroid hormone receptor (PTH/PTHrP receptor) signaling in osteoblasts in unloading-induced bone loss using transgenic mice. Hind limb unloading by tail suspension reduced bone mass in wild-type mice. In contrast, signaling by constitutively active PTH/PTHrP receptor (caPPR), whose expression was regulated by the osteoblast-specific Col1a1 promoter (Col1a1-caPPR), suppressed unloading-induced reduction in bone mass in these transgenic mice. In Col1a1-caPPR transgenic (Tg) mice, hind limb unloading suppressed bone formation parameters in vivo and mineralized nodule formation in vitro similarly to those observed in wild-type mice. In addition, serum osteocalcin levels and mRNA expression levels of type I collagen, Runx2 and Osterix in bone were suppressed by unloading in both wild-type mice and Tg mice. However, in contrast to unloading-induced enhancement of bone resorption parameters in wild-type mice, Col1a1-caPPR signaling suppressed, rather than enhanced, osteoclast number and osteoclast surface as well as urinary deoxypyridinoline excretion upon unloading. Col1a1-caPPR signaling also suppressed mRNA expression levels of RANK and c-fms in bone upon unloading. Although the M-CSF and monocyte chemoattractant protein 1 (MCP-1) mRNA levels were enhanced in control Tg mice, these levels were suppressed in unloaded Tg mice. These results indicated that constitutive activation of PTH/PTHrP receptor signaling in osteoblastic cells suppresses unloading-induced bone loss specifically through the regulation of osteoclastic activity. PMID:17500070

  20. Organic amendments to avocado crops induce suppressiveness and influence the composition and activity of soil microbial communities.

    Science.gov (United States)

    Bonilla, Nuria; Vida, Carmen; Martínez-Alonso, Maira; Landa, Blanca B; Gaju, Nuria; Cazorla, Francisco M; de Vicente, Antonio

    2015-05-15

    One of the main avocado diseases in southern Spain is white root rot caused by the fungus Rosellinia necatrix Prill. The use of organic soil amendments to enhance the suppressiveness of natural soil is an inviting approach that has successfully controlled other soilborne pathogens. This study tested the suppressive capacity of different organic amendments against R. necatrix and analyzed their effects on soil microbial communities and enzymatic activities. Two-year-old avocado trees were grown in soil treated with composted organic amendments and then used for inoculation assays. All of the organic treatments reduced disease development in comparison to unamended control soil, especially yard waste (YW) and almond shells (AS). The YW had a strong effect on microbial communities in bulk soil and produced larger population levels and diversity, higher hydrolytic activity and strong changes in the bacterial community composition of bulk soil, suggesting a mechanism of general suppression. Amendment with AS induced more subtle changes in bacterial community composition and specific enzymatic activities, with the strongest effects observed in the rhizosphere. Even if the effect was not strong, the changes caused by AS in bulk soil microbiota were related to the direct inhibition of R. necatrix by this amendment, most likely being connected to specific populations able to recolonize conducive soil after pasteurization. All of the organic amendments assayed in this study were able to suppress white root rot, although their suppressiveness appears to be mediated differentially. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  1. High Throughput Measurement of Locomotor Sensitization to Volatilized Cocaine in Drosophila melanogaster

    Directory of Open Access Journals (Sweden)

    Ana Filošević

    2018-02-01

    Full Text Available Drosophila melanogaster can be used to identify genes with novel functional roles in neuronal plasticity induced by repeated consumption of addictive drugs. Behavioral sensitization is a relatively simple behavioral output of plastic changes that occur in the brain after repeated exposures to drugs of abuse. The development of screening procedures for genes that control behavioral sensitization has stalled due to a lack of high-throughput behavioral tests that can be used in genetically tractable organism, such as Drosophila. We have developed a new behavioral test, FlyBong, which combines delivery of volatilized cocaine (vCOC to individually housed flies with objective quantification of their locomotor activity. There are two main advantages of FlyBong: it is high-throughput and it allows for comparisons of locomotor activity of individual flies before and after single or multiple exposures. At the population level, exposure to vCOC leads to transient and concentration-dependent increase in locomotor activity, representing sensitivity to an acute dose. A second exposure leads to further increase in locomotion, representing locomotor sensitization. We validate FlyBong by showing that locomotor sensitization at either the population or individual level is absent in the mutants for circadian genes period (per, Clock (Clk, and cycle (cyc. The locomotor sensitization that is present in timeless (tim and pigment dispersing factor (pdf mutant flies is in large part not cocaine specific, but derived from increased sensitivity to warm air. Circadian genes are not only integral part of the neural mechanism that is required for development of locomotor sensitization, but in addition, they modulate the intensity of locomotor sensitization as a function of the time of day. Motor-activating effects of cocaine are sexually dimorphic and require a functional dopaminergic transporter. FlyBong is a new and improved method for inducing and measuring locomotor

  2. Suppressed PHA activation of T lymphocytes in simulated microgravity is restored by direct activation of protein kinase C

    Science.gov (United States)

    Cooper, D.; Pellis, N. R.; McIntire, L. V. (Principal Investigator)

    1998-01-01

    Utilizing clinostatic rotating wall vessel (RWV) bioreactors that simulate aspects of microgravity, we found phytohemagglutinin (PHA) responsiveness to be almost completely diminished. Activation marker expression was significantly reduced in RWV cultures. Furthermore, cytokine secretion profiles suggested that monocytes are not as adversely affected by simulated microgravity as T cells. Reduced cell-cell and cell-substratum interactions may play a role in the loss of PHA responsiveness because placing peripheral blood mononuclear cells (PBMC) within small collagen beads did partially restore PHA responsiveness. However, activation of purified T cells with cross-linked CD2/CD28 and CD3/CD28 antibody pairs was completely suppressed in the RWV, suggesting a defect in signal transduction. Activation of purified T cells with PMA and ionomycin was unaffected by RWV culture. Furthermore, sub-mitogenic doses of PMA alone but not ionomycin alone restored PHA responsiveness of PBMC in RWV culture. Thus our data indicate that during polyclonal activation the signaling pathways upstream of PKC activation are sensitive to simulated microgravity.

  3. Livers with constitutive mTORC1 activity resist steatosis independent of feedback suppression of Akt.

    Directory of Open Access Journals (Sweden)

    Heidi L Kenerson

    Full Text Available Insulin resistance is an important contributing factor in non-alcoholic fatty liver disease. AKT and mTORC1 are key components of the insulin pathway, and play a role in promoting de novo lipogenesis. However, mTORC1 hyperactivity per se does not induce steatosis in mouse livers, but instead, protects against high-fat diet induced steatosis. Here, we investigate the in vivo mechanism of steatosis-resistance secondary to mTORC1 activation, with emphasis on the role of S6K1-mediated feedback inhibition of AKT. Mice with single or double deletion of Tsc1 and/or S6k1 in a liver-specific or whole-body manner were generated to study glucose and hepatic lipid metabolism between the ages of 6-14 weeks. Following 8 weeks of high-fat diet, the Tsc1-/-;S6k1-/- mice had lower body weights but higher liver TG levels compared to that of the Tsc1-/- mice. However, the loss of S6k1 did not relieve feedback inhibition of Akt activity in the Tsc1-/- livers. To overcome Akt suppression, Pten was deleted in Tsc1-/- livers, and the resultant mice showed improved glucose tolerance compared with the Tsc1-/- mice. However, liver TG levels were significantly reduced in the Tsc1-/-;Pten-/- mice compared to the Pten-/- mice, which was restored with rapamycin. We found no correlation between liver TG and serum NEFA levels. Expression of lipogenic genes (Srebp1c, Fasn were elevated in the Tsc1-/-;Pten-/- livers, but this was counter-balanced by an up-regulation of Cpt1a involved in fatty acid oxidation and the anti-oxidant protein, Nrf2. In summary, our in vivo models showed that mTORC1-induced resistance to steatosis was dependent on S6K1 activity, but not secondary to AKT suppression. These findings confirm that AKT and mTORC1 have opposing effects on hepatic lipid metabolism in vivo.

  4. [Stable isotopes of Mg2+ as activators of the suppressed ATP-generating function of mitochondria].

    Science.gov (United States)

    Kuznetsov, D A; Arkhantel'skiĭ, S E; Berdieva, A G; Markarian, A A; Khasigov, P Z; Gatagonova, T M; Ktsova, S A; Orlova, M A

    2005-01-01

    The ATP-generating activity of rat myocardial mitochondria and intramitochondrial creatine kinase was examined as a function of the isotopy of the incubation medium magnesium pool. The study was performed using in vitro systems prepared from the hearts of animals injected with 1-methylnicotine amide, which suppresses the NAD (NADP)-dependent reactions in vivo. It was shown that the presence of the 25Mg paramagnetic cations essential by compensates for the intramitochondrial ATP deficiency caused by the 1-methyl-nicotine amide-induced blockade of oxidative phosphorylation. This effect is hardey achievable in systems where the magnesium pool consists of isotopes with a zero nuclear spin (24Mg, 26Mg). The restoration of mitochondrial ATP synthesis involves the participation of creatine kinase since the activity of the latter does not depend on 1-methyl-nicotine amide. In this case, the high efficiency of this restaration seems to be a spin-selective phenomenon which requires predominantly 25Mg2+ cations. A possible meaning of the data for further studies on the mechanisms of enzymatic catalysis regulation is discussed.

  5. MST2 phosphorylation at serine 385 in mitosis inhibits its tumor suppressing activity.

    Science.gov (United States)

    Chen, Xingcheng; Chen, Yuanhong; Dong, Jixin

    2016-12-01

    Mammalian sterile 20-like kinase 1/2 (MST1/2) are core tumor suppressors in the Hippo signaling pathway. MST1/2 have been shown to regulate mitotic progression. Here, we report a novel mechanism for phospho-regulation of MST2 in mitosis and its biological significance in cancer. We found that the mitotic kinase cyclin-dependent kinase 1 (CDK1) phosphorylates MST2 in vitro and in vivo at serine 385 during antimitotic drug-induced G2/M phase arrest. This phosphorylation occurs transiently during unperturbed mitosis. Mitotic phosphorylation of MST2 does not affect its kinase activity or Hippo-YAP signaling. We further showed that mitotic phosphorylation-deficient mutant MST2-S385A possesses higher activity in suppressing cell proliferation and anchorage-independent growth in vitro and tumorigenesis in vivo. Together, our findings reveal a novel layer of regulation for MST2 in mitosis and its role in tumorigenesis. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Blocking Myristoylation of Src Inhibits Its Kinase Activity and Suppresses Prostate Cancer Progression.

    Science.gov (United States)

    Kim, Sungjin; Alsaidan, Omar Awad; Goodwin, Octavia; Li, Qianjin; Sulejmani, Essilvo; Han, Zhen; Bai, Aiping; Albers, Thomas; Beharry, Zanna; Zheng, Y George; Norris, James S; Szulc, Zdzislaw M; Bielawska, Alicja; Lebedyeva, Iryna; Pegan, Scott D; Cai, Houjian

    2017-12-15

    Protein N -myristoylation enables localization to membranes and helps maintain protein conformation and function. N -myristoyltransferases (NMT) catalyze co- or posttranslational myristoylation of Src family kinases and other oncogenic proteins, thereby regulating their function. In this study, we provide genetic and pharmacologic evidence that inhibiting the N -myristoyltransferase NMT1 suppresses cell-cycle progression, proliferation, and malignant growth of prostate cancer cells. Loss of myristoylation abolished the tumorigenic potential of Src and its synergy with androgen receptor in mediating tumor invasion. We identified the myristoyl-CoA analogue B13 as a small-molecule inhibitor of NMT1 enzymatic activity. B13 exposure blocked Src myristoylation and Src localization to the cytoplasmic membrane, attenuating Src-mediated oncogenic signaling. B13 exerted its anti-invasive and antitumor effects against prostate cancer cells, with minimal toxic side-effects in vivo Structural optimization based on structure-activity relationships enabled the chemical synthesis of LCL204, with enhanced inhibitory potency against NMT1. Collectively, our results offer a preclinical proof of concept for the use of protein myristoylation inhibitors as a strategy to block prostate cancer progression. Cancer Res; 77(24); 6950-62. ©2017 AACR . ©2017 American Association for Cancer Research.

  7. RAG-induced DNA lesions activate proapoptotic BIM to suppress lymphomagenesis in p53-deficient mice

    Science.gov (United States)

    Herold, Marco J.

    2016-01-01

    Neoplastic transformation is driven by oncogenic lesions that facilitate unrestrained cell expansion and resistance to antiproliferative signals. These oncogenic DNA lesions, acquired through errors in DNA replication, gene recombination, or extrinsically imposed damage, are thought to activate multiple tumor suppressive pathways, particularly apoptotic cell death. DNA damage induces apoptosis through well-described p53-mediated induction of PUMA and NOXA. However, loss of both these mediators (even together with defects in p53-mediated induction of cell cycle arrest and cell senescence) does not recapitulate the tumor susceptibility observed in p53−/− mice. Thus, potentially oncogenic DNA lesions are likely to also trigger apoptosis through additional, p53-independent processes. We found that loss of the BH3-only protein BIM accelerated lymphoma development in p53-deficient mice. This process was negated by concomitant loss of RAG1/2-mediated antigen receptor gene rearrangement. This demonstrates that BIM is critical for the induction of apoptosis caused by potentially oncogenic DNA lesions elicited by RAG1/2-induced gene rearrangement. Furthermore, this highlights the role of a BIM-mediated tumor suppressor pathway that acts in parallel to the p53 pathway and remains active even in the absence of wild-type p53 function, suggesting this may be exploited in the treatment of p53-deficient cancers. PMID:27621418

  8. Fem1b promotes ubiquitylation and suppresses transcriptional activity of Gli1.

    Science.gov (United States)

    Gilder, Andrew S; Chen, Yong-Bin; Jackson, Ramon J; Jiang, Jin; Maher, Joseph F

    2013-10-25

    The mammalian Fem1b gene encodes a homolog of FEM-1, a protein in the sex-determination pathway of the nematode Caenorhabditis elegans. Fem1b and FEM-1 proteins each contain a VHL-box motif that mediates their interaction with certain E3 ubiquitin ligase complexes. In C. elegans, FEM-1 negatively regulates the transcription factor TRA-1, and functions as an E3 ubiquitin ligase substrate recognition subunit to target TRA-1 for ubiquitylation. TRA-1 is homologous to the mammalian Gli1 protein, a transcription factor that mediates Hedgehog signaling as well as having Hedgehog-independent functions. Whether the interaction between nematode FEM-1 and TRA-1 proteins is conserved, between corresponding mammalian homologs, has not been reported. Herein, we show that Fem1b interacts with Gli1 within cells, and directly binds Gli1. Fem1b also promotes ubiquitylation of Gli1, suppresses transcriptional activation by Gli1, and attenuates an oncogenic Gli1 autoregulatory loop in cancer cells, all dependent on the VHL-box of Fem1b. These findings have implications for understanding the cellular functions of Fem1b, and the regulation of Gli1 oncoprotein activity. Copyright © 2013 Elsevier Inc. All rights reserved.

  9. Evodia alkaloids suppress gluconeogenesis and lipogenesis by activating the constitutive androstane receptor.

    Science.gov (United States)

    Yu, Lushan; Wang, Zhangting; Huang, Minmin; Li, Yingying; Zeng, Kui; Lei, Jinxiu; Hu, Haihong; Chen, Baian; Lu, Jing; Xie, Wen; Zeng, Su

    2016-09-01

    The constitutive androstane receptor (CAR) is a key sensor in xenobiotic detoxification and endobiotic metabolism. Increasing evidence suggests that CAR also plays a role in energy metabolism by suppressing the hepatic gluconeogenesis and lipogenesis. In this study, we investigated the effects of two evodia alkaloids, rutaecarpine (Rut) and evodiamine (Evo), on gluconeogenesis and lipogenesis through their activation of the human CAR (hCAR). We found that both Rut and Evo exhibited anti-lipogenic and anti-gluconeogenic effects in the hyperlipidemic HepG2 cells. Both compounds can potently activate hCAR, and treatment of cells with hCAR antagonists reversed the anti-lipogenic and anti-gluconeogenic effects of Rut and Evo. The anti-gluconeogenic effect of Rut and Evo was due to the CAR-mediated inhibition of the recruitment of forkhead box O1 (FoxO1) and hepatocyte nuclear factor 4α (HNF4α) onto the phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) gene promoters. In vivo, we showed that treatment of mice with Rut improved glucose tolerance in a CAR-dependent manner. Our results suggest that the evodia alkaloids Rut and Evo may have a therapeutic potential for the treatment of hyperglycemia and type 2 diabetes. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. Nur77 modulates hepatic lipid metabolism through suppression of SREBP1c activity

    International Nuclear Information System (INIS)

    Pols, Thijs W.H.; Ottenhoff, Roelof; Vos, Mariska; Levels, Johannes H.M.; Quax, Paul H.A.; Meijers, Joost C.M.; Pannekoek, Hans; Groen, Albert K.; Vries, Carlie J.M. de

    2008-01-01

    NR4A nuclear receptors are induced in the liver upon fasting and regulate hepatic gluconeogenesis. Here, we studied the role of nuclear receptor Nur77 (NR4A1) in hepatic lipid metabolism. We generated mice expressing hepatic Nur77 using adenoviral vectors, and demonstrate that these mice exhibit a modulation of the plasma lipid profile and a reduction in hepatic triglyceride. Expression analysis of >25 key genes involved in lipid metabolism revealed that Nur77 inhibits SREBP1c expression. This results in decreased SREBP1c activity as is illustrated by reduced expression of its target genes stearoyl-coA desaturase-1, mitochondrial glycerol-3-phosphate acyltransferase, fatty acid synthase and the LDL receptor, and provides a mechanism for the physiological changes observed in response to Nur77. Expression of LXR target genes Abcg5 and Abcg8 is reduced by Nur77, and may suggest involvement of LXR in the inhibitory action of Nur77 on SREBP1c expression. Taken together, our study demonstrates that Nur77 modulates hepatic lipid metabolism through suppression of SREBP1c activity

  11. Determinants of locomotor disability in people aged 55 years and over: The Rotterdam study

    International Nuclear Information System (INIS)

    Odding, Else; Valkenburg, Hans A.; Stam, Hendrik J.; Hofman, Albert

    2001-01-01

    Locomotor disability, as defined by difficulties in activities of daily living related to lower limb function, can be the consequence of diseases and impairments of the cardiovascular, pulmonary, nervous, sensory and musculoskeletal system. We estimated the associations between specific diseases and impairments and locomotor disability, and the proportion of disability attributable to each condition, controlling for age and comorbidity. The Rotterdam Study is a prospective follow-up study among people aged 55 years and over in the general population. Locomotor disability in 1219 men and 1856 women was assessed with the Stanford Health Assessment Questionnaire. Diseases and impairments were radiological osteoarthritis, pain of the hips and knees, morning stiffness, fractures, hypertension, vascular disease, ischemic heart disease, stroke, heart failure, chronic obstructive pulmonary disease (COPD), depression, Parkinson's disease, osteoporosis, diabetes mellitus, overweight, and low vision. Adjusted odds ratios, etiologic and attributable fractions were calculated for locomotor disability. The occurrence of locomotor disability can partly be ascribed to joint pain, COPD, morning stiffness, diabetes and heart failure in both men and women. In addition in women osteoarthritis, osteoporosis, low vision, fractures, stroke and Parkinson's disease are significant etiologic fractions. In men with morning stiffness, joint pain, heart failure, diabetes mellitus, and COPD a significant proportion of their disability is attributable to this impairment. In women this was the case for Parkinson's disease, morning stiffness, low vision, heart failure, joint pain, diabetes, radiological osteoarthritis, stroke, COPD, osteoporosis, and fractures of the lower limbs, in that order. We conclude that locomotor complaints, heart failure, COPD and diabetes mellitus contribute considerably to locomotor disability in non-institutionalized elderly people

  12. Chronic recordings reveal tactile stimuli can suppress spontaneous activity of neurons in somatosensory cortex of awake and anesthetized primates.

    Science.gov (United States)

    Qi, Hui-Xin; Reed, Jamie L; Franca, Joao G; Jain, Neeraj; Kajikawa, Yoshinao; Kaas, Jon H

    2016-04-01

    In somatosensory cortex, tactile stimulation within the neuronal receptive field (RF) typically evokes a transient excitatory response with or without postexcitatory inhibition. Here, we describe neuronal responses in which stimulation on the hand is followed by suppression of the ongoing discharge. With the use of 16-channel microelectrode arrays implanted in the hand representation of primary somatosensory cortex of New World monkeys and prosimian galagos, we recorded neuronal responses from single units and neuron clusters. In 66% of our sample, neuron activity tended to display suppression of firing when regions of skin outside of the excitatory RF were stimulated. In a small proportion of neurons, single-site indentations suppressed firing without initial increases in response to any of the tested sites on the hand. Latencies of suppressive responses to skin indentation (usually 12-34 ms) were similar to excitatory response latencies. The duration of inhibition varied across neurons. Although most observations were from anesthetized animals, we also found similar neuron response properties in one awake galago. Notably, suppression of ongoing neuronal activity did not require conditioning stimuli or multi-site stimulation. The suppressive effects were generally seen following single-site skin indentations outside of the neuron's minimal RF and typically on different digits and palm pads, which have not often been studied in this context. Overall, the characteristics of widespread suppressive or inhibitory response properties with and without initial facilitative or excitatory responses add to the growing evidence that neurons in primary somatosensory cortex provide essential processing for integrating sensory stimulation from across the hand. Copyright © 2016 the American Physiological Society.

  13. Inhibitory effect of putranjivain A on allergic inflammation through suppression of mast cell activation

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Hui-Hun; Park, Seung-Bin; Lee, Soyoung [CMRI, Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 700-422 (Korea, Republic of); Kwon, Taeg Kyu [Department of Immunology, School of Medicine, Keimyung University, Daegu 704-701 (Korea, Republic of); Shin, Tae-Yong [College of Pharmacy, Woosuk University, Jeonju 565-701 (Korea, Republic of); Park, Pil-Hoon; Lee, Seung-Ho [College of Pharmacy, Youngnam University, Kyungsan 712-749 (Korea, Republic of); Kim, Sang-Hyun, E-mail: shkim72@knu.ac.kr [CMRI, Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 700-422 (Korea, Republic of)

    2014-02-01

    A great number of people are suffering from allergic inflammatory disease such as asthma, atopic dermatitis, and sinusitis. Therefore discovery of drugs for the treatment of these diseases is an important subject in human health. Putranjivain A (PJA), member of ellagitannin, is known to possess beneficial effects including anti-cancer and anti-viral activities. The aim of the present study was to elucidate whether PJA modulates the allergic inflammatory reaction and to study its possible mechanisms of action using mast cell-based in vitro and in vivo models. The study was performed in anaphylaxis mouse model and cultured mast cells. PJA inhibited the expression of pro-inflammatory cytokines in immunoglobulin E-stimulated mast cells. PJA reduced this expression by inhibiting nuclear factor (NF)-κB and nuclear factor of activated T cell. The oral administration of PJA reduced systemic and cutaneous anaphylaxis, the release of serum histamine, and the expression of the histamine H{sub 1} receptor. In addition, PJA attenuated the activation of mast cells. PJA inhibited the release of histamine from various types of mast cells by the suppression of intracellular calcium. The inhibitory activity of PJA on the allergic reaction was similar to that of disodium cromoglycate, a known anti-allergic drug. These results suggest that PJA can facilitate the prevention or treatment of allergic inflammatory diseases mediated by mast cells. - Highlights: • PJA reduced the degranulation of mast cells. • PJA inhibited the production of inflammatory cytokines. • The effect of PJA on allergic reaction was comparable to the DSCG. • PJA might be a candidate for the treatment of allergic inflammatory diseases.

  14. Antiplatelet Aggregation Activity of Walnut Hull Extract via Suppression of Reactive Oxygen Species Generation and Caspase Activation.

    Science.gov (United States)

    Meshkini, Azadeh; Tahmasbi, Masoumeh

    2017-06-01

    Walnut hull (wal hull) is an agricultural by-product that is widely used in traditional medicine for alleviating pain and treating skin diseases, however, recently it has gained much attention in modern pharmacology due to its antioxidant properties. The current study was aimed to determine the total phenolic, flavonoid, and tannin content of Persian wal hull extract and evaluate its biological effects on platelet function. Experimental data showed that acetone extract of wal hulls has a high content of polyphenolic compounds and antioxidant properties. The analytical study of crude extract by gas chromatography-mass spectrometry demonstrated different types of high- and low-molecular-weight compounds that are basically and biologically important. Moreover, an in vitro study revealed that wal hull extract at a concentration of 50 μg/mL inhibited thrombin-induced platelet aggregation and protein secretion by 50%, without any cytotoxic effects on platelets. The examined extract suppressed reactive oxygen species generation and also caspase activation in thrombin-stimulated platelets. Identically, N-acetylcysteine inhibited the increase of reactive oxygen species level induced by thrombin in platelets, and supported a link between cellular redox status and caspase activation in activated platelets. Presumably, the antiplatelet activity of wal hull extract is related to its polyphenolic compounds and their antioxidant properties. Therefore, wal hulls can be considered as a candidate for thrombotic disorders. Copyright © 2017. Published by Elsevier B.V.

  15. Antiplatelet Aggregation Activity of Walnut Hull Extract via Suppression of Reactive Oxygen Species Generation and Caspase Activation

    Directory of Open Access Journals (Sweden)

    Azadeh Meshkini

    2017-06-01

    Full Text Available Walnut hull (wal hull is an agricultural by-product that is widely used in traditional medicine for alleviating pain and treating skin diseases, however, recently it has gained much attention in modern pharmacology due to its antioxidant properties. The current study was aimed to determine the total phenolic, flavonoid, and tannin content of Persian wal hull extract and evaluate its biological effects on platelet function. Experimental data showed that acetone extract of wal hulls has a high content of polyphenolic compounds and antioxidant properties. The analytical study of crude extract by gas chromatography–mass spectrometry demonstrated different types of high- and low-molecular-weight compounds that are basically and biologically important. Moreover, an in vitro study revealed that wal hull extract at a concentration of 50 μg/mL inhibited thrombin-induced platelet aggregation and protein secretion by 50%, without any cytotoxic effects on platelets. The examined extract suppressed reactive oxygen species generation and also caspase activation in thrombin-stimulated platelets. Identically, N-acetylcysteine inhibited the increase of reactive oxygen species level induced by thrombin in platelets, and supported a link between cellular redox status and caspase activation in activated platelets. Presumably, the antiplatelet activity of wal hull extract is related to its polyphenolic compounds and their antioxidant properties. Therefore, wal hulls can be considered as a candidate for thrombotic disorders.

  16. Copper suppresses abscisic acid catabolism and catalase activity, and inhibits seed germination of rice.

    Science.gov (United States)

    Ye, Nenghui; Li, Haoxuan; Zhu, Guohui; Liu, Yinggao; Liu, Rui; Xu, Weifeng; Jing, Yu; Peng, Xinxiang; Zhang, Jianhua

    2014-11-01

    Although copper (Cu) is an essential micronutrient for plants, a slight excess of Cu in soil can be harmful to plants. Unfortunately, Cu contamination is a growing problem all over the world due to human activities, and poses a soil stress to plant development. As one of the most important biological processes, seed germination is sensitive to Cu stress. However, little is known about the mechanism of Cu-induced inhibition of seed germination. In the present study, we investigated the relationship between Cu and ABA which is the predominant regulator of seed germination. Cu at a concentration of 30 µM effectively inhibited germination of rice caryopsis. ABA content in germinating seeds under copper stress was also higher than that under control conditions. Quantitative real-time PCR (qRT-PCR) revealed that Cu treatment reduced the expression of OsABA8ox2, a key gene of ABA catabolism in rice seeds. In addition, both malondialdehyde (MDA) and H2O2 contents were increased by Cu stress in the germinating seeds. Antioxidant enzyme assays revealed that only catalase activity was reduced by excess Cu, which was consistent with the mRNA profile of OsCATa during seed germination under Cu stress. Together, our results demonstrate that suppression of ABA catabolism and catalase (CAT) activity by excess Cu leads to the inhibition of seed germination of rice. © The Author 2014. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  17. Cystatin E/M suppresses legumain activity and invasion of human melanoma

    Directory of Open Access Journals (Sweden)

    Fodstad Øystein

    2010-01-01

    Full Text Available Abstract Background High activity of cysteine proteases such as legumain and the cathepsins have been shown to facilitate growth and invasion of a variety of tumor types. In breast cancer, several recent studies have indicated that loss of the cysteine protease inhibitor cystatin E/M leads to increased growth and metastasis. Although cystatin E/M is normally expressed in the skin, its role in cysteine protease regulation and progression of malignant melanoma has not been studied. Methods A panel of various non-melanoma and melanoma cell lines was used. Cystatin E/M and C were analyzed in cell media by immunoblotting and ELISA. Legumain, cathepsin B and L were analyzed in cell lysates by immunoblotting and their enzymatic activities were analyzed by peptide substrates. Two melanoma cell lines lacking detectable secretion of cystatin E/M were transfected with a cystatin E/M expression plasmid (pCST6, and migration and invasiveness were studied by a Matrigel invasion assay. Results Cystatin E/M was undetectable in media from all established melanoma cell lines examined, whereas strong immunobands were detected in two of five primary melanoma lines and in two of six lines derived from patients with metastatic disease. Among the four melanoma lines secreting cystatin E/M, the glycosylated form (17 kD was predominant compared to the non-glycosylated form (14 kD. Legumain, cathepsin B and L were expressed and active in most of the cell lines, although at low levels in the melanomas expressing cystatin E/M. In the melanoma lines where cystatin E/M was secreted, cystatin C was generally absent or expressed at a very low level. When melanoma cells lacking secretion of cystatin E/M were transfected with pCST6, their intracellular legumain activity was significantly inhibited. In contrast, cathepsin B activity was not affected. Furthermore, invasion was suppressed in cystatin E/M over-expressing melanoma cell lines as measured by the transwell Matrigel

  18. LPV Modeling and Control for Active Flutter Suppression of a Smart Airfoil

    Science.gov (United States)

    Al-Hajjar, Ali M. H.; Al-Jiboory, Ali Khudhair; Swei, Sean Shan-Min; Zhu, Guoming

    2018-01-01

    In this paper, a novel technique of linear parameter varying (LPV) modeling and control of a smart airfoil for active flutter suppression is proposed, where the smart airfoil has a groove along its chord and contains a moving mass that is used to control the airfoil pitching and plunging motions. The new LPV modeling technique is proposed that uses mass position as a scheduling parameter to describe the physical constraint of the moving mass, in addition the hard constraint at the boundaries is realized by proper selection of the parameter varying function. Therefore, the position of the moving mass and the free stream airspeed are considered the scheduling parameters in the study. A state-feedback based LPV gain-scheduling controller with guaranteed H infinity performance is presented by utilizing the dynamics of the moving mass as scheduling parameter at a given airspeed. The numerical simulations demonstrate the effectiveness of the proposed LPV control architecture by significantly improving the performance while reducing the control effort.

  19. Entada phaseoloides extract suppresses hepatic gluconeogenesis via activation of the AMPK signaling pathway.

    Science.gov (United States)

    Zheng, Tao; Hao, Xincai; Wang, Qibin; Chen, Li; Jin, Si; Bian, Fang

    2016-12-04

    The seed of Entada phaseoloides (L.) Merr. (Entada phaseoloides) has been long used as a folk medicine for the treatment of Diabetes mellitus by Chinese ethnic minorities. Recent reports have demonstrated that total saponins from Entada phaseoloides (TSEP) could reduce fasting blood glucose in type 2 diabetic rats. However, the mechanism has not been fully elucidated. The aim of this study was to explore the underlying mechanisms of TSEP on type 2 Diabetes mellitus (T2DM). Primary mouse hepatocytes and HepG2 cells were used to investigate the effects of TSEP on gluconeogenesis. After treatment with TSEP, glucose production, genes expression levels of Glucose-6-phosphatase (G6pase) and Phosphoenoylpyruvate carboxykinase (Pepck) were detected. The efficacy and underlying mechanism of TSEP on AMP-activated protein kinase (AMPK) signaling pathway were determinated. TSEP significantly inhibited glucose production and the gluconeogenic gene expression. Treatment with TSEP elevated the phosphorylation of AMPK, which in turn promoted the phosphorylation of acetyl coenzyme A (ACC) and Akt/glycogen synthase kinase 3β (GSK3β), respectively. Furthermore, TSEP reduced lipid accumulation and improved insulin sensitivity in hepatocytes. These findings provide evidence that TSEP exerts an antidiabetic effect by suppressing hepatic gluconeogenesis via the AMPK signaling pathway. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  20. Neuropeptide Y acts in the paraventricular nucleus to suppress sympathetic nerve activity and its baroreflex regulation

    Science.gov (United States)

    Cassaglia, Priscila A; Shi, Zhigang; Li, Baoxin; Reis, Wagner L; Clute-Reinig, Nicholas M; Stern, Javier E; Brooks, Virginia L

    2014-01-01

    Neuropeptide Y (NPY), a brain neuromodulator that has been strongly implicated in the regulation of energy balance, also acts centrally to inhibit sympathetic nerve activity (SNA); however, the site and mechanism of action are unknown. In chloralose-anaesthetized female rats, nanoinjection of NPY into the paraventricular nucleus of the hypothalamus (PVN) dose-dependently suppressed lumbar SNA (LSNA) and its baroreflex regulation, and these effects were blocked by prior inhibition of NPY Y1 or Y5 receptors. Moreover, PVN injection of Y1 and Y5 receptor antagonists in otherwise untreated rats increased basal and baroreflex control of LSNA, indicating that endogenous NPY tonically inhibits PVN presympathetic neurons. The sympathoexcitation following blockade of PVN NPY inhibition was eliminated by prior PVN nanoinjection of the melanocortin 3/4 receptor inhibitor SHU9119. Moreover, presympathetic neurons, identified immunohistochemically using cholera toxin b neuronal tract tracing from the rostral ventrolateral medulla (RVLM), express NPY Y1 receptor immunoreactivity, and patch-clamp recordings revealed that both NPY and α–melanocyte-stimulating hormone (α-MSH) inhibit and stimulate, respectively, PVN–RVLM neurons. Collectively, these data suggest that PVN NPY inputs converge with α-MSH to influence presympathetic neurons. Together these results identify endogenous NPY as a novel and potent inhibitory neuromodulator within the PVN that may contribute to changes in SNA that occur in states associated with altered energy balance, such as obesity and pregnancy. PMID:24535439

  1. Short-Term Genetic Selection for Adolescent Locomotor Sensitivity to Delta9-Tetrahydrocannabinol (THC).

    Science.gov (United States)

    Kasten, Chelsea R; Zhang, Yanping; Mackie, Ken; Boehm, Stephen L

    2018-03-17

    Cannabis use is linked to positive and negative outcomes. Identifying genetic targets of susceptibility to the negative effects of cannabinoid use is of growing importance. The current study sought to complete short-term selective breeding for adolescent sensitivity and resistance to the locomotor effects of a single 10 mg/kg THC dose in the open field. Selection for THC-locomotor sensitivity was moderately heritable, with the greatest estimates of heritability seen in females from the F2 to S3 generations. Selection for locomotor sensitivity also resulted in increased anxiety-like activity in the open field. These results are the first to indicate that adolescent THC-locomotor sensitivity can be influenced via selective breeding. Development of lines with a genetic predisposition for THC-sensitivity or resistance to locomotor effects allow for investigation of risk factors, differences in consequences of THC use, identification of correlated behavioral responses, and detection of genetic targets that may contribute to heightened cannabinoid sensitivity.

  2. Locomotor activity of Cycloneda sanguinea (Coleoptera: Coccinellidae exposed to volatile semiochemicals and to direct contact with the odour source Actividad locomotriz de Cycloneda sanguinea (Coleoptera: Coccinellidae expuesta a semioquímicos volátiles y al contacto directo con la fuente de olor

    Directory of Open Access Journals (Sweden)

    Guillermo E. Heit

    2007-12-01

    Full Text Available Cycloneda sanguinea (Linnaeus (Coleoptera: Coccinellidae is an opportunistic polyphagous predator and when aphids dominate its menu, a complex foraging behaviour can be expected. An active movement characterized by a high locomotor activity plays an important role in the search of this prey. The behaviour of C. sanguinea adults exposed to volatile semiochemicals emitted by Capsicum annuum Linnaeus (Solanaceae substrates, healthy or infested with Myzus persicae (Sulzer (Hemiptera: Aphididae, or in direct contact with these substrates was here analyzed. The treatments evaluated were: A high aphid-infested pepper leaves, B low aphid-infested pepper leaves, C healthy pepper leaves and D control. Locomotor activity was not significantly different among treatments when C. sanguinea was exposed only to the volatiles. However, when adults were placed in direct contact with the evaluated substrates, statistically significant differences were found among treatments. These preliminary results could indicate that the sole presence of an olfactory stimulus could not be sufficient to modulate a different locomotor pattern in C. sanguinea.Cycloneda sanguinea (Linnaeus (Coleoptera: Coccinellidae es un predador polífago oportunista y cuando su menú está dominado por áfidos, es esperable un comportamiento complejo de forrajeo. Un movimiento activo, caracterizado por alta actividad locomotriz, juega un rol importante en la búsqueda de esta presa. En este trabajo se analizó el comportamiento de adultos de C. sanguinea expuestos a los semioquímicos volátiles, emitidos por sustratos de Capsicum annuum Linnaeus (Solanaceae sanos o infestados con Myzus persicae (Sulzer (Hemiptera: Aphididae, o simplemente puestos en contacto directo con esos sustratos. Los tratamientos evaluados fueron: A hojas de pimiento infestadas con alta densidad de áfidos, B hojas de pimiento infestadas con baja densidad de áfidos, C hojas de pimiento sanas y D control. La actividad

  3. Jasmonate inhibits COP1 activity to suppress hypocotyl elongation and promote cotyledon opening in etiolated Arabidopsis seedlings.

    Science.gov (United States)

    Zheng, Yuyu; Cui, Xuefei; Su, Liang; Fang, Shuang; Chu, Jinfang; Gong, Qingqiu; Yang, Jianping; Zhu, Ziqiang

    2017-06-01

    A germinating seedling undergoes skotomorphogenesis to emerge from the soil and reach for light. During this phase, the cotyledons are closed, and the hypocotyl elongates. Upon exposure to light, the seedling rapidly switches to photomorphogenesis by opening its cotyledons and suppressing hypocotyl elongation. The E3 ubiquitin ligase CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1) is critical for maintaining skotomorphogenesis. Here, we report that jasmonate (JA) suppresses hypocotyl elongation and stimulates cotyledon opening in etiolated seedlings, partially phenocopying cop1 mutants in the dark. We also find that JA stabilizes several COP1-targeted transcription factors in a COP1-dependent manner. RNA-seq analysis further defines a JA-light co-modulated and cop1-dependent transcriptome, which is enriched for auxin-responsive genes and genes participating in cell wall modification. JA suppresses COP1 activity through at least two distinct mechanisms: decreasing COP1 protein accumulation in the nucleus; and reducing the physical interaction between COP1 and its activator, SUPPRESSOR OF PHYTOCHROME A-105 1 (SPA1). Our work reveals that JA suppresses COP1 activity to stabilize COP1 targets, thereby inhibiting hypocotyl elongation and stimulating cotyledon unfolding in etiolated Arabidopsis seedlings. © 2017 The Authors The Plant Journal © 2017 John Wiley & Sons Ltd.

  4. Suppression and excitation of MHD activity with an electrically polarized electrode at the TCABR tokamak plasma edge

    International Nuclear Information System (INIS)

    Nascimento, I.C.; Kuznetsov, Yu.K.; Guimaraes-Filho, Z.O.; Chamaa-Neto, I. El; Usuriaga, O.; Fonseca, A.M.M.; Galvao, R.M.O.; Caldas, I.L.; Severo, J.H.F.; Semenov, I.B.; Ribeiro, C.; Heller, M.V.P.; Bellintani, V.; Elizondo, J.I.; Sanada, E.

    2007-01-01

    Two reproducible regimes of tokamak operation, with excitation or suppression of MHD activity can be obtained using a voltage-biased electrode inside the edge of the TCABR tokamak. The experiment was carried out adjusting the tokamak parameters to obtain two types of discharges: with strong or weak MHD activity, without biasing in both cases. The plasma current was adjusted to cover a range of safety factor from 2.9 up to 3.5, so that when biasing was applied the magnetic island (3,1) could interact with the edge barrier. The application of biasing in subsequent discharges of each type resulted in excitation or suppression of the MHD activity. The results show that the dominant modes are m = 2, n = 1 and m = 3, n = 1 for excitation and partial suppression, respectively. In both regimes a strong decrease in the radial electric field is detected with destruction of the transport barrier and of the improved confinement caused by different mechanisms. The measurements include temporal behaviour of edge transport, turbulence, poloidal electric and magnetic fields, edge density, radial electric fields and radial profile of H α line intensity. The explanation of the excitation and suppression processes is discussed in the paper

  5. Auricular Acupuncture May Suppress Epileptic Seizures via Activating the Parasympathetic Nervous System: A Hypothesis Based on Innovative Methods

    Directory of Open Access Journals (Sweden)

    Wei He

    2012-01-01

    Full Text Available Auricular acupuncture is a diagnostic and treatment system based on normalizing the body's dysfunction. An increasing number of studies have demonstrated that auricular acupuncture has a significant effect on inducing parasympathetic tone. Epilepsy is a neurological disorder consisting of recurrent seizures resulting from excessive, uncontrolled electrical activity in the brain. Autonomic imbalance demonstrating an increased sympathetic activity and a reduced parasympathetic activation is involved in the development and progress of epileptic seizures. Activation of the parasympathetic nervous system such as vagus nerve stimulation has been used for the treatment of intractable epilepsy. Here, we propose that auricular acupuncture may suppress epileptic seizures via activating the parasympathetic nervous system.

  6. Auricular Acupuncture May Suppress Epileptic Seizures via Activating the Parasympathetic Nervous System: A Hypothesis Based on Innovative Methods.

    Science.gov (United States)

    He, Wei; Rong, Pei-Jing; Li, Liang; Ben, Hui; Zhu, Bing; Litscher, Gerhard

    2012-01-01

    Auricular acupuncture is a diagnostic and treatment system based on normalizing the body's dysfunction. An increasing number of studies have demonstrated that auricular acupuncture has a significant effect on inducing parasympathetic tone. Epilepsy is a neurological disorder consisting of recurrent seizures resulting from excessive, uncontrolled electrical activity in the brain. Autonomic imbalance demonstrating an increased sympathetic activity and a reduced parasympathetic activation is involved in the development and progress of epileptic seizures. Activation of the parasympathetic nervous system such as vagus nerve stimulation has been used for the treatment of intractable epilepsy. Here, we propose that auricular acupuncture may suppress epileptic seizures via activating the parasympathetic nervous system.

  7. An in-beam Compton-suppressed Ge spectrometer for nondestructive neutron activation analysis

    International Nuclear Information System (INIS)

    Zaghloul, R.; Abd El-Haleam, A.; Mostafa, M.; Gantner, E.; Ache, H.J.

    1993-04-01

    A high-efficiency compton background suppressed gamma-ray spectrometer by anti-coincidence counting with a NaI(Tl)-shield around a central HPGe-detector for in-beam prompt gamma-ray neutron activation analysis (AC-PGNAA) using a Cf-252 neutron source has been designed and built to provide simultaneous anti-coincidence spectrometry of natural, industrial and environmental samples. The spectrometer consists of a high-purity germanium detector as the main detector and a large volume cylindrical NaI(Tl) detector as a guard detector. The assembly has the ability to measure instantaneously, simultaneously and nondestructively bulk samples up to about 50 cm 3 . Major constituent elements in several rocks and minerals such as H, B, N, Na, Mg, Al, Si, Cl, K, Ca, P, S, Ti, Fe, Sm, Nd, Mn and Gd can be determined, while oxygen cannot be measured due to its small capture cross section (0.27 mb). Several important minor and trace elements such as B, Cd and Hg beside the low residual activity, rare earths and short-lived isotopes could be detected. The sensitivity of the AC-PGNAA technique is limited by the available neutron flux at the target matrix and the neutron absorption cross section of the elements of interest. PGNAA has the advantage to estimate the constituent elements which are difficult to be measured through the delayed gamm-ray measurements such as B, Bi, C, H, P, Tl, Be, Cl and S in industrial and reference materials and those elements which are transformed into other stable isotopes when undergoing neutron capture. The design of the spectrometer assembly, its properties and performance are described

  8. Coriandrum sativum Suppresses Aβ42-Induced ROS Increases, Glial Cell Proliferation, and ERK Activation.

    Science.gov (United States)

    Liu, Quan Feng; Jeong, Haemin; Lee, Jang Ho; Hong, Yoon Ki; Oh, Youngje; Kim, Young-Mi; Suh, Yoon Seok; Bang, Semin; Yun, Hye Sup; Lee, Kyungho; Cho, Sung Man; Lee, Sung Bae; Jeon, Songhee; Chin, Young-Won; Koo, Byung-Soo; Cho, Kyoung Sang

    2016-01-01

    Alzheimer's disease (AD), the most common neurodegenerative disease, has a complex and widespread pathology that is characterized by the accumulation of amyloid [Formula: see text]-peptide (A[Formula: see text]) in the brain and various cellular abnormalities, including increased oxidative damage, an amplified inflammatory response, and altered mitogen-activated protein kinase signaling. Based on the complex etiology of AD, traditional medicinal plants with multiple effective components are alternative treatments for patients with AD. In the present study, we investigated the neuroprotective effects of an ethanol extract of Coriandrum sativum (C. sativum) leaves on A[Formula: see text] cytotoxicity and examined the molecular mechanisms underlying the beneficial effects. Although recent studies have shown the benefits of the inhalation of C. sativum oil in an animal model of AD, the detailed molecular mechanisms by which C. sativum exerts its neuroprotective effects are unclear. Here, we found that treatment with C. sativum extract increased the survival of both A[Formula: see text]-treated mammalian cells and [Formula: see text]42-expressing flies. Moreover, C. sativum extract intake suppressed [Formula: see text]-induced cell death in the larval imaginal disc and brain without affecting A[Formula: see text]42 expression and accumulation. Interestingly, the increases in reactive oxygen species levels and glial cell number in AD model flies were reduced by C. sativum extract intake. Additionally, C. sativum extract inhibited the epidermal growth factor receptor- and A[Formula: see text]-induced phosphorylation of extracellular signal-regulated kinase (ERK). The constitutively active form of ERK abolished the protective function of C. sativum extract against the [Formula: see text]-induced eye defect phenotype in Drosophila. Taken together, these results suggest that C. sativum leaves have antioxidant, anti-inflammatory, and ERK signaling inhibitory properties that

  9. Midazolam more effectively suppresses sympathetic activations and reduces stress feelings during mental arithmetic task than propofol.

    Science.gov (United States)

    Tsugayasu, Rie; Handa, Toshiyuki; Kaneko, Yuzuru; Ichinohe, Tatsuya

    2010-03-01

    The aim of the present study was to examine the effect of intravenous midazolam and propofol sedation on autonomic nervous activities during psychological stress, and whether these results are associated with changes in subjective stress feelings. Seven healthy male volunteers were included in a randomized crossover manner. The heart rate (HR), HR variability, arterial oxygen saturation, and bispectral index value were continuously monitored. A mental arithmetic task for 7 minutes was given with or without intravenous sedation with midazolam or propofol. A bispectral index value of 75 to 85 and an Observer's Assessment of Alertness/Sedation score of 4 were the targeted sedation level in both groups. HR variability was assessed using the power spectral analysis (low-frequency [LF] and high-frequency [HF] components and LF/HF ratio). The faces anxiety scale was used to grade their stress feelings after each mental arithmetic task. During the mental arithmetic task with intravenous sedation, no differences were found in the bispectral index values, arterial oxygen saturation, or the results of the mental arithmetic task between the 2 groups. The HR, LF/HF ratio, and normalized unit LF increased, and the normalized unit HF decreased in both groups. However, the percentage of changes in LF/HF ratio, normalized unit LF, and normalized unit HF were smaller in the midazolam group. In addition, the reduction in faces anxiety scale was greater in the midazolam group. These results suggest that midazolam more effectively suppresses sympathetic nervous activation and reduces subjective stress feelings during a mental arithmetic task than propofol. Copyright (c) 2010 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

  10. Ritmos de actividad locomotora y uso de las cuevas en condiciones seminaturales en Ctenomys talarum (Rodentia, Octodontidae) Rhythms of locomotor activity and burrow use under seminatural conditions in Ctenomys talarum (Rodentia, Octodontidae)

    OpenAIRE

    FACUNDO LUNA; C. DANIEL ANTINUCHI; CRISTINA BUSCH

    2000-01-01

    Ctenomys es un género de roedores subterráneos que vive en sistemas de galerías cerrados a la superficie del suelo y por lo tanto lleva a cabo la mayoría de sus actividades en ausencia de luz. Sin embargo a diferencia de otros roedores subterráneos sus salidas a la superficie son frecuentes. En este trabajo fueron evaluadas, en Ctenomys talarum (Thomas, 1898) la existencia y las características de los ritmos locomotores de actividad para distintas condiciones experimentales. Además, fueron an...

  11. New ways enhancing the vital activity of plants in order to increase crop yields and to suppress radionuclide accumulation

    International Nuclear Information System (INIS)

    Goncharova, N. V; Zebrakova, I. V.; Matsko, V. P.; Kislushko, P. M.

    1994-01-01

    After Chernobyl nuclear accident it has become very important to seek new ways of enhancing the vital activity of plants in order to increase crop yields and to suppress radionuclide accumulation. It is found that by optimizing the vital activity processes in plants, is possible to reduce radionuclide uptake. A great number of biologically active compounds have been tested, which increased the disease resistance of plants and simultaneously activated the physiological and biochemical processes that control the transport of micro- and macroelements (radionuclide included) and their 'soil-root-stem-leaf' redistribution. (author)

  12. Kurarinol induces hepatocellular carcinoma cell apoptosis through suppressing cellular signal transducer and activator of transcription 3 signaling

    Energy Technology Data Exchange (ETDEWEB)

    Shu, Guangwen; Yang, Jing; Zhao, Wenhao; Xu, Chan; Hong, Zongguo; Mei, Zhinan; Yang, Xinzhou, E-mail: xinzhou_yang@hotmail.com

    2014-12-01

    Kurarinol is a flavonoid isolated from roots of the medical plant Sophora flavescens. However, its cytotoxic activity against hepatocellular carcinoma (HCC) cells and toxic effects on mammalians remain largely unexplored. Here, the pro-apoptotic activities of kurarinol on HCC cells and its toxic impacts on tumor-bearing mice were evaluated. The molecular mechanisms underlying kurarinol-induced HCC cell apoptosis were also investigated. We found that kurarinol dose-dependently provoked HepG2, Huh-7 and H22 HCC cell apoptosis. In addition, kurarinol gave rise to a considerable decrease in the transcriptional activity of signal transducer and activator of transcription 3 (STAT3) in HCC cells. Suppression of STAT3 signaling is involved in kurarinol-induced HCC cell apoptosis. In vivo studies showed that kurarinol injection substantially induced transplanted H22 cell apoptosis with low toxic impacts on tumor-bearing mice. Similarly, the transcriptional activity of STAT3 in transplanted tumor tissues was significantly suppressed after kurarinol treatment. Collectively, our current research demonstrated that kurarinol has the capacity of inducing HCC cell apoptosis both in vitro and in vivo with undetectable toxic impacts on the host. Suppressing STAT3 signaling is implicated in kurarinol-mediated HCC cell apoptosis. - Highlights: • Kurarinol induces hepatocellular carcinoma (HCC) cell apoptosis. • Kurarinol induces HCC cell apoptosis via inhibiting STAT3. • Kurarinol exhibits low toxic effects on tumor-bearing animals.

  13. Kurarinol induces hepatocellular carcinoma cell apoptosis through suppressing cellular signal transducer and activator of transcription 3 signaling

    International Nuclear Information System (INIS)

    Shu, Guangwen; Yang, Jing; Zhao, Wenhao; Xu, Chan; Hong, Zongguo; Mei, Zhinan; Yang, Xinzhou

    2014-01-01

    Kurarinol is a flavonoid isolated from roots of the medical plant Sophora flavescens. However, its cytotoxic activity against hepatocellular carcinoma (HCC) cells and toxic effects on mammalians remain largely unexplored. Here, the pro-apoptotic activities of kurarinol on HCC cells and its toxic impacts on tumor-bearing mice were evaluated. The molecular mechanisms underlying kurarinol-induced HCC cell apoptosis were also investigated. We found that kurarinol dose-dependently provoked HepG2, Huh-7 and H22 HCC cell apoptosis. In addition, kurarinol gave rise to a considerable decrease in the transcriptional activity of signal transducer and activator of transcription 3 (STAT3) in HCC cells. Suppression of STAT3 signaling is involved in kurarinol-induced HCC cell apoptosis. In vivo studies showed that kurarinol injection substantially induced transplanted H22 cell apoptosis with low toxic impacts on tumor-bearing mice. Similarly, the transcriptional activity of STAT3 in transplanted tumor tissues was significantly suppressed after kurarinol treatment. Collectively, our current research demonstrated that kurarinol has the capacity of inducing HCC cell apoptosis both in vitro and in vivo with undetectable toxic impacts on the host. Suppressing STAT3 signaling is implicated in kurarinol-mediated HCC cell apoptosis. - Highlights: • Kurarinol induces hepatocellular carcinoma (HCC) cell apoptosis. • Kurarinol induces HCC cell apoptosis via inhibiting STAT3. • Kurarinol exhibits low toxic effects on tumor-bearing animals

  14. Suppression of Natural Killer Cell Activity by Regulatory NKT10 Cells Aggravates Alcoholic Hepatosteatosis

    Directory of Open Access Journals (Sweden)

    Kele Cui

    2017-10-01

    Full Text Available We and others have found that the functions of hepatic natural killer (NK cells are inhibited but invariant NKT (iNKT cells become activated after alcohol drinking, leaving a possibility that there exists interplay between NK cells and iNKT cells during alcoholic liver disease. Here, in a chronic plus single-binge ethanol consumption mouse model, we observed that NK cells and interferon-γ (IFN-γ protected against ethanol-induced liver steatosis, as both wild-type (WT mice treated with anti-asialo GM1 antibody and IFN-γ-deficient GKO mice developed more severe alcoholic fatty livers. As expected, IFN-γ could directly downregulate lipogenesis in primary hepatocytes in vitro. On the contrary, iNKT cell-deficient Jα18−/− or interleukin-10 (IL-10−/− mice showed fewer alcoholic steatosis, along with the recovered number and IFN-γ release of hepatic NK cells, and exogenous IL-10 injection was sufficient to compensate for iNKT cell deficiency. Furthermore, NK cell depletion in Jα18−/− or IL-10−/− mice caused more severe hepatosteatosis, implying NK cells are the direct effector cells to inhibit liver steatosis. Importantly, adoptive transfer of iNKT cells purified from normal but not IL-10−/− mice resulted in suppression of the number and functions of NK cells and aggravated alcoholic liver injury in Jα18−/− mice, indicating that IL-10-producing iNKT (NKT10 cells are the regulators on NK cells. Conclusion: Ethanol exposure-triggered NKT10 cells antagonize the protective roles of NK cells in alcoholic hepatosteatosis.

  15. Vorinostat Modulates the Imbalance of T Cell Subsets, Suppresses Macrophage Activity, and Ameliorates Experimental Autoimmune Uveoretinitis.

    Science.gov (United States)

    Fang, Sijie; Meng, Xiangda; Zhang, Zhuhong; Wang, Yang; Liu, Yuanyuan; You, Caiyun; Yan, Hua

    2016-03-01

    The purpose of the study was to investigate the anti-inflammatory efficiency of vorinostat, a histone deacetylase inhibitor, in experimental autoimmune uveitis (EAU). EAU was induced in female C57BL/6J mice immunized with interphotoreceptor retinoid-binding protein peptide. Vorinostat or the control treatment, phosphate-buffered saline, was administrated orally from 3 days before immunization until euthanasia at day 21 after immunization. The clinical and histopathological scores of mice were graded, and the integrity of the blood-retinal barrier was examined by Evans blue staining. T helper cell subsets were measured by flow cytometry, and the macrophage functions were evaluated with immunohistochemistry staining and immunofluorescence assays. The mRNA levels of tight junction proteins were measured by qRT-PCR. The expression levels of intraocular cytokines and transcription factors were examined by western blotting. Vorinostat relieved both clinical and histopathological manifestations of EAU in our mouse model, and the BRB integrity was maintained in vorinostat-treated mice, which had less vasculature leakage and higher mRNA and protein expressions of tight junction proteins than controls. Moreover, vorinostat repressed Th1 and Th17 cells and increased Th0 and Treg cells. Additionally, the INF-γ and IL-17A expression levels were significantly decreased, while the IL-10 level was increased by vorinostat treatment. Furthermore, due to the reduced TNF-α level, the macrophage activity was considerably inhibited in EAU mice. Finally, transcription factors, including STAT1, STAT3, and p65, were greatly suppressed by vorinostat treatment. Our data suggest that vorinostat might be a potential anti-inflammatory agent in the management of uveitis and other autoimmune inflammatory diseases.

  16. Optimizing learning of a locomotor task: amplifying errors as needed.

    Science.gov (United States)

    Marchal-Crespo, Laura; López-Olóriz, Jorge; Jaeger, Lukas; Riener, Robert

    2014-01-01

    Research on motor learning has emphasized that errors drive motor adaptation. Thereby, several researchers have proposed robotic training strategies that amplify movement errors rather than decrease them. In this study, the effect of different robotic training strategies that amplify errors on learning a complex locomotor task was investigated. The experiment was conducted with a one degree-of freedom robotic stepper (MARCOS). Subjects were requested to actively coordinate their legs in a desired gait-like pattern in order to track a Lissajous figure presented on a visual display. Learning with three different training strategies was evaluated: (i) No perturbation: the robot follows the subjects' movement without applying any perturbation, (ii) Error amplification: existing errors were amplified with repulsive forces proportional to errors, (iii) Noise disturbance: errors were evoked with a randomly-varying force disturbance. Results showed that training without perturbations was especially suitable for a subset of initially less-skilled subjects, while error amplification seemed to benefit more skilled subjects. Training with error amplification, however, limited transfer of learning. Random disturbing forces benefited learning and promoted transfer in all subjects, probably because it increased attention. These results suggest that learning a locomotor task can be optimized when errors are randomly evoked or amplified based on subjects' initial skill level.

  17. Role of the 5-HT2A receptor in the locomotor hyperactivity produced by phenylalkylamine hallucinogens in mice

    Science.gov (United States)

    Halberstadt, Adam L.; Powell, Susan B.; Geyer, Mark A.

    2014-01-01

    The 5-HT2A receptor mediates the effects of serotonergic hallucinogens and may play a role in the pathophysiology of certain psychiatric disorders, including schizophrenia. Given these findings, there is a need for animal models to assess the behavioral effects of 5-HT2A receptor activation. Our previous studies demonstrated that the phenylalkylamine hallucinogen and 5-HT2A/2C agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) produces dose-dependent effects on locomotor activity in C57BL/6J mice, increasing activity at low to moderate doses and reducing activity at high doses. DOI did not increase locomotor activity in 5-HT2A knockout mice, indicating the effect is a consequence of 5-HT2A receptor activation. Here, we tested a series of phenylalkylamine hallucinogens in C57BL/6J mice using the Behavioral Pattern Monitor (BPM) to determine whether these compounds increase locomotor activity by activating the 5-HT2A receptor. Low doses of mescaline, 2,5-dimethoxy-4-ethylamphetamine (DOET), 2,5-dimethoxy-4-propylamphetamine (DOPR), 2,4,5-trimethoxyamphetamine (TMA-2), and the conformationally restricted phenethylamine (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine (TCB-2) increased locomotor activity. By contrast, the non-hallucinogenic phenylalkylamine 2,5-dimethoxy-4-tert-butylamphetamine (DOTB) did not alter locomotor activity at any dose tested (0.1-10 mg/kg i.p.). The selective 5-HT2A antagonist M100907 blocked the locomotor hyperactivity induced by mescaline and TCB-2. Similarly, mescaline and TCB-2 did not increase locomotor activity in 5-HT2A knockout mice. These results confirm that phenylalkylamine hallucinogens increase locomotor activity in mice and demonstrate that this effect is mediated by 5-HT2A receptor activation. Thus, locomotor hyperactivity in mice can be used to assess phenylalkylamines for 5-HT2A agonist activity and hallucinogen-like behavioral effects. These studies provide additional support for the link between 5-HT2A activation and

  18. Disruption of locomotor adaptation with repetitive transcranial magnetic stimulation over the motor cortex

    DEFF Research Database (Denmark)

    Choi, Julia Tsok Lam; Bouyer, Laurent J; Nielsen, Jens Bo

    2015-01-01

    Locomotor patterns are adapted on a trial-and-error basis to account for predictable dynamics. Once a walking pattern is adapted, the new calibration is stored and must be actively de-adapted. Here, we tested the hypothesis that storage of newly acquired ankle adaptation in walking is dependent o...

  19. Impairment of the organization of locomotor and exploratory behaviors in bile duct-ligated rats

    DEFF Research Database (Denmark)

    Leke, Renata; de Oliveira, Diogo L; Mussulini, Ben Hur M.

    2012-01-01

    Hepatic encephalopathy (HE) arises from acute or chronic liver diseases and leads to several problems, including motor impairment. Animal models of chronic liver disease have extensively investigated the mechanisms of this disease. Impairment of locomotor activity has been described in different ...

  20. Initial locomotor sensitivity to cocaine varies widely among inbred mouse strains.

    Science.gov (United States)

    Wiltshire, T; Ervin, R B; Duan, H; Bogue, M A; Zamboni, W C; Cook, S; Chung, W; Zou, F; Tarantino, L M

    2015-03-01

    Initial sensitivity to psychostimulants can predict subsequent use and abuse in humans. Acute locomotor activation in response to psychostimulants is commonly used as an animal model of initial drug sensitivity and has been shown to have a substantial genetic component. Identifying the specific genetic differences that lead to phenotypic differences in initial drug sensitivity can advance our understanding of the processes that lead to addiction. Phenotyping inbred mouse strain panels are frequently used as a first step for studying the genetic architecture of complex traits. We assessed locomotor activation following a single, acute 20 mg/kg dose of cocaine (COC) in males from 45 inbred mouse strains and observed significant phenotypic variation across strains indicating a substantial genetic component. We also measured levels of COC, the active metabolite, norcocaine and the major inactive metabolite, benzoylecgonine, in plasma and brain in the same set of inbred strains. Pharmacokinetic (PK) and behavioral data were significantly correlated, but at a level that indicates that PK alone does not account for the behavioral differences observed across strains. Phenotypic data from this reference population of inbred strains can be utilized in studies aimed at examining the role of psychostimulant-induced locomotor activation on drug reward and reinforcement and to test theories about addiction processes. Moreover, these data serve as a starting point for identifying genes that alter sensitivity to the locomotor stimulatory effects of COC. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  1. Immature spinal locomotor output in children with Cerebral Palsy

    Directory of Open Access Journals (Sweden)

    Germana Cappellini

    2016-10-01

    Full Text Available Detailed descriptions of gait impairments have been reported in cerebral palsy (CP, but it is still unclear how maturation of the spinal motoneuron output is affected. Spatiotemporal alpha-motoneuron activation during walking can be assessed by mapping the electromyographic activity profiles from several, simultaneously recorded muscles onto the anatomical rostrocaudal location of the motoneuron pools in the spinal cord, and by means of factor analysis of the muscle activity profiles. Here, we analysed gait kinematics and EMG activity of 11 pairs of bilateral muscles with lumbosacral innervation in 35 children with CP (19 diplegic, 16 hemiplegic, 2-12 years and 33 typically developing (TD children (1-12 years. TD children showed a progressive reduction of EMG burst durations and a gradual reorganization of the spatiotemporal motoneuron output with increasing age. By contrast, children with CP showed very limited age-related changes of EMG durations and motoneuron output, as well as of limb intersegmental coordination and foot trajectory control (on both sides for diplegic children and the affected side for hemiplegic children. Factorization of the EMG signals revealed a comparable structure of the motor output in children with CP and TD children, but significantly wider temporal activation patterns in children with CP, resembling the patterns of much younger TD infants. A similar picture emerged when considering the spatiotemporal maps of alpha-motoneuron activation. Overall, the results are consistent with the idea that early injuries to developing motor regions of the brain substantially affect the maturation of the spinal locomotor output and consequently the future locomotor behaviour.

  2. Suppressive effect of AMP-activated protein kinase on the epithelial-mesenchymal transition in retinal pigment epithelial cells.

    Directory of Open Access Journals (Sweden)

    Ryo Matoba

    Full Text Available The epithelial-mesenchymal transition (EMT in retinal pigment epithelial (RPE cells plays a central role in the development of proliferative vitreoretinopathy (PVR. The purpose of this study was to investigate the effect of AMP-activated protein kinase (AMPK, a key regulator of energy homeostasis, on the EMT in RPE cells. In this study, EMT-associated formation of cellular aggregates was induced by co-stimulation of cultured ARPE-19 cells with tumor necrosis factor (TNF-α (10 ng/ml and transforming growth factor (TGF-β2 (5 ng/ml. 5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR, a potent activator of AMPK, significantly suppressed TNF-α and TGF-β2-induced cellular aggregate formation (p < 0.01. Dipyridamole almost completely reversed the suppressive effect of AICAR, whereas 5'-amino-5'-deoxyadenosine restored aggregate formation by approximately 50%. AICAR suppressed the downregulation of E-cadherin and the upregulation of fibronectin and α-smooth muscle actin by TNF-α and TGF-β2. The levels of matrix metalloproteinase (MMP-2, MMP-9, interleukin-6, and vascular endothelial growth factor were significantly decreased by AICAR. Activation of the mitogen-activated protein kinase and mammalian target of rapamycin pathways, but not the Smad pathway, was inhibited by AICAR. These findings indicate that AICAR suppresses the EMT in RPE cells at least partially via activation of AMPK. AMPK is a potential target molecule for the prevention and treatment of PVR, so AICAR may be a promising candidate for PVR therapy.

  3. Heat treatment enhances the NO-suppressing and peroxynitrite-intercepting activities of kumquat (Fortunella margarita Swingle) peel.

    Science.gov (United States)

    Lin, Chih-Cheng; Hung, Pi-Fang; Ho, Su-Chen

    2008-07-01

    In Taiwan, folk remedies containing dried kumquats (Fortunella margarita Swingle) are used to cure inflammatory respiratory disorders. The induction of inducible nitric oxide (NO) synthase in inflammatory cells and increased airway production of NO and peroxynitrite, its derivative, are key events in such disorders. Although heat is known to affect the antioxidant activity of citrus peels, the effects of dehydration and heating on NO suppression and on the interception of peroxynitrite are unclear. We determined the NO-suppressing activities of freeze-dried, oven-dried, and heat-treated kumquat extracts by measuring their inhibition of NO production in lipopolysaccharide-activated RAW 264.7 macrophages. Furthermore, we evaluated the attenuation of peroxynitrite-mediated nitrotyrosine formation in albumin. Heating, but not oven drying, enhanced the ability of kumquat peels to suppress NO and intercept peroxynitrite, as compared with freeze drying. However, heat treatment and oven drying of kumquat flesh attenuated these activities; these effects were at least partially attributed to heat-susceptible ascorbate. Copyright © 2007 Elsevier Ltd. All rights reserved.

  4. Carvacrol, a component of thyme oil, activates PPARα and γ and suppresses COX-2 expression[S

    Science.gov (United States)

    Hotta, Mariko; Nakata, Rieko; Katsukawa, Michiko; Hori, Kazuyuki; Takahashi, Saori; Inoue, Hiroyasu

    2010-01-01

    Cyclooxygenase-2 (COX-2), the rate-limiting enzyme in prostaglandin biosynthesis, plays a key role in inflammation and circulatory homeostasis. Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors belonging to the nuclear receptor superfamily and are involved in the control of COX-2 expression, and vice versa. Here, we show that COX-2 promoter activity was suppressed by essential oils derived from thyme, clove, rose, eucalyptus, fennel, and bergamot in cell-based transfection assays using bovine arterial endothelial cells. Moreover, from thyme oil, we identified carvacrol as a major component of the suppressor of COX-2 expression and an activator of PPARα and γ. PPARγ-dependent suppression of COX-2 promoter activity was observed in response to carvacrol treatment. In human macrophage-like U937 cells, carvacrol suppressed lipopolysaccharide-induced COX-2 mRNA and protein expression, suggesting that carvacrol regulates COX-2 expression through its agonistic effect on PPARγ. These results may be important in understanding the antiinflammatory and antilifestyle-related disease properties of carvacrol. PMID:19578162

  5. Cis-urocanic acid, a sunlight-induced immunosuppressive factor, activates immune suppression via the 5-HT2A receptor

    Science.gov (United States)

    Walterscheid, Jeffrey P.; Nghiem, Dat X.; Kazimi, Nasser; Nutt, Leta K.; McConkey, David J.; Norval, Mary; Ullrich, Stephen E.

    2006-01-01

    Exposure to UV radiation induces skin cancer and suppresses the immune response. To induce immune suppression, the electromagnetic energy of UV radiation must be absorbed by an epidermal photoreceptor and converted into a biologically recognizable signal. Two photoreceptors have been recognized: DNA and trans-urocanic acid (UCA). Trans-UCA is normally found in the outermost layer of skin and isomerizes to the cis isomer upon exposure to UV radiation. Although UCA was identified as a UV photoreceptor years ago, and many have documented its ability to induce immune suppression, its exact mode of action remains elusive. Particularly vexing has been the identity of the molecular pathway by which cis-UCA mediates immune suppression. Here we provide evidence that cis-UCA binds to the serotonin [5-hydroxytryptamine (5-HT)] receptor with relatively high affinity (Kd = 4.6 nM). Anti-cis-UCA antibody precipitates radiolabeled 5-HT, and the binding is inhibited by excess 5-HT and/or excess cis-UCA. Similarly, anti-5-HT antibody precipitates radiolabeled cis-UCA, and the binding is inhibited by excess 5-HT or excess cis-UCA. Calcium mobilization was activated when a mouse fibroblast line, stably transfected with the human 5-HT2A receptor, was treated with cis-UCA. Cis-UCA-induced calcium mobilization was blocked with a selective 5-HT2A receptor antagonist. UV- and cis-UCA-induced immune suppression was blocked by antiserotonin antibodies or by treating the mice with 5-HT2A receptor antagonists. Our findings identify cis-UCA as a serotonin receptor ligand and indicate that the immunosuppressive effects of cis-UCA and UV radiation are mediated by activation of the 5-HT2A receptor. PMID:17085585

  6. ASH1L Suppresses Matrix Metalloproteinase through Mitogen-activated Protein Kinase Signaling Pathway in Pulpitis.

    Science.gov (United States)

    Bei, Yin; Tianqian, Hui; Fanyuan, Yu; Haiyun, Luo; Xueyang, Liao; Jing, Yang; Chenglin, Wang; Ling, Ye

    2017-02-01

    with in vitro results, ASH1L was found in increased quantities in experimental dental pulpitis tissue. ASH1L knockdown markedly up-regulated the occurrence of MMP-1, MMP-2, and MMP-13. It also exercised an impact on the enzymatic activity of MMP-2 in HDPCs that had been stimulated with TNF-α. ASH1L knockdown activated the MAPK signal pathway in TNF-α-triggered HDPCs, the inhibition of which reversed the induction of MMPs. Our research identifies a mechanism by which ASH1L suppresses the occurrence and operation of MMPs during pulpitis. It does this through the MAPK pathway. Copyright © 2016 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

  7. Arabidopsis cryptochrome 1 interacts with SPA1 to suppress COP1 activity in response to blue light

    Science.gov (United States)

    Liu, Bin; Zuo, Zecheng; Liu, Hongtao; Liu, Xuanming; Lin, Chentao

    2011-01-01

    Plant photoreceptors mediate light suppression of the E3 ubiquitin ligase COP1 (CONSTITUTIVE PHOTOMORPHOGENIC 1) to affect gene expression and photomorphogenesis. However, how photoreceptors mediate light regulation of COP1 activity remains unknown. We report here that Arabidopsis blue-light receptor cryptochrome 1 (CRY1) undergoes blue-light-dependent interaction with the COP1-interacting protein SPA1 (SUPPRESSOR OF PHYTOCHROME A). We further show that the CRY1–SPA1 interaction suppresses the SPA1–COP1 interaction and COP1-dependent degradation of the transcription factor HY5. These results are consistent with a hypothesis that photoexcited CRY1 interacts with SPA1 to modulate COP1 activity and plant development. PMID:21511871

  8. The involvement of noradrenergic mechanisms in the suppressive effects of diazepam on the hypothalamicpituitary- adrenal axis activity in female rats

    OpenAIRE

    Švob Štrac, Dubravka; Muck-Šeler, Dorotea

    2012-01-01

    Aim To elucidate the involvement of noradrenergic system in the mechanism by which diazepam suppresses basal hypothalamic-pituitary-adrenal (HPA) axis activity. Methods Plasma corticosterone and adrenocorticotropic hormone (ACTH) levels were determined in female rats treated with diazepam alone, as well as with diazepam in combination with clonidine (α2-adrenoreceptor agonist), yohimbine (α2-adrenoreceptor antagonist), alpha-methylp- tyrosine (α-MPT, an inhibitor of ca...

  9. Activation of glucocorticoid receptors in Müller glia is protective to retinal neurons and suppresses microglial reactivity

    OpenAIRE

    Gallina, Donika; Zelinka, Christopher Paul; Cebulla, Colleen; Fischer, Andy J.

    2015-01-01

    Reactive microglia and macrophages are prevalent in damaged retinas. Glucocorticoid signaling is known to suppress inflammation and the reactivity of microglia and macrophages. In the vertebrate retina, the glucocorticoid receptor (GCR) is known to be activated and localized to the nuclei of Müller glia (Gallina et al., 2014). Accordingly, we investigated how signaling through GCR influences the survival of neurons using the chick retina in vivo as a model system. We applied intraocular injec...

  10. Design of a Ge-NaI(Tl) Compton suppression spectrometer and its use in neutron activation analysis

    International Nuclear Information System (INIS)

    Petra, M.; Swift, G.; Landsberger, S.

    1990-01-01

    A Compton suppression spectrometer consisting of a germanium detector surrounded by a NaI(Tl) shield and its performance are described. The system reduces the Compton continuum, thus making possible the identification of low-intensity peaks. This allows the determination of small amounts of various elements in biological and environmental materials following neutron activation. Representative results for arsenic in biological materials are presented. (orig.)

  11. Dopa therapy and action impulsivity: subthreshold error activation and suppression in Parkinson's disease

    NARCIS (Netherlands)

    Fluchère, F.; Deveaux, M.; Burle, B.; Vidal, F.; van den Wildenberg, W.P.M.; Witjas, T.; Eusebio, A.; Azulay, J.-P.; Hasbroucq, T.

    2015-01-01

    Rationale: Impulsive actions entail (1) capture of the motor system by an action impulse, which is an urge to act and (2) failed suppression of that impulse in order to prevent a response error. Several studies indicate that dopaminergic treatment can induce action impulsivity in patients diagnosed

  12. Multi-walled carbon nanotubes suppress potassium channel activities in PC12 cells

    Science.gov (United States)

    Xu, Haifei; Bai, Juan; Meng, Jie; Hao, Wei; Xu, Haiyan; Cao, Ji-Min

    2009-07-01

    The advancement in nanotechnology has produced technological and conceptual breakthroughs but the effects nanomaterials have on organisms at the cellular level are poorly understood. Here we report that carboxyl-terminated multi-walled carbon nanotubes (MWCNTs) act as antagonists of three types of potassium channels as assessed by whole-cell patch clamp electrophysiology on undifferentiated pheochromocytoma (PC12) cells. Our results showed that carboxyl-terminated MWCNTs suppress the current densities of Ito, IK and IK1 in a time-dependent and irreversible manner. The suppressions were most distinct 24 h after incubation with MWCNTs. However, MWCNTs did not significantly change the expression levels of reactive oxygen species (ROS) or intracellular free calcium and also did not alter the mitochondrial membrane potential (ΔΨm) in PC12 cells. These results suggest that oxidative stress was not involved in the MWCNTs suppression of Ito, IK and IK1 current densities. Nonetheless, the suppression of potassium currents by MWCNTs will impact on electrical signaling of excitable cells such as neurons and muscles.

  13. Functional relations between locomotor performance traits in spiders and implications for evolutionary hypotheses

    Directory of Open Access Journals (Sweden)

    Taylor Phillip W

    2010-11-01

    Full Text Available Abstract Background Locomotor performance in ecologically relevant activities is often linked to individual fitness. Recent controversy over evolution of extreme sexual size dimorphism (SSD in spiders centres on the relationship between size and locomotor capacity in males. Advantages for large males running over horizontal surfaces and small males climbing vertically have been proposed. Models have implicitly treated running and climbing as functionally distinct activities and failed to consider the possibility that they reflect common underlying capacities. Findings We examine the relationship between maximum climbing and running performance in males of three spider species. Maximum running and climbing speeds were positively related in two orb-web spiders with high SSD (Argiope keyserlingi and Nephila plumipes, indicating that for these species assays of running and climbing largely reveal the same underlying capacities. Running and climbing speeds were not related in a jumping spider with low SSD (Jacksonoides queenslandica. We found no evidence of a performance trade-off between these activities. Conclusions In the web-spiders A. keyserlingi and N. plumipes good runners were also good climbers. This indicates that climbing and running largely represent a single locomotor performance characteristic in these spiders, but this was not the case for the jumping spider J. queenslandica. There was no evidence of a trade-off between maximum running and climbing speeds in these spiders. We highlight the need to establish the relationship between apparently disparate locomotor activities when testing alternative hypotheses that yield predictions about different locomotor activities. Analysis of slopes suggests greater potential for an evolutionary response on performance in the horizontal compared to vertical context in these spiders.

  14. Broccoli and watercress suppress matrix metalloproteinase-9 activity and invasiveness of human MDA-MB-231 breast cancer cells

    International Nuclear Information System (INIS)

    Rose, Peter; Huang, Qing; Ong, Choon Nam; Whiteman, Matt

    2005-01-01

    A high dietary intake of cruciferous vegetables has been associated with a reduction in numerous human pathologies particularly cancer. In the current study, we examined the inhibitory effects of broccoli (Brassica oleracea var. italica) and watercress (Rorripa nasturtium aquaticum) extracts on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cancer cell invasion and matrix metalloproteinase-9 activity using human MDA-MB-231 breast cancer cells. Aberrant overexpression of matrix metalloproteinases, including metalloproteinase-9, is associated with increased invasive potential in cancer cell lines. Our results demonstrate that extracts of broccoli and Rorripa suppressed TPA-induced MMP-9 activity and invasiveness in a concentration dependant manner as determined by zymographic analysis. Furthermore, fractionation of individual extracts followed by liquid chromatography mass spectroscopy analysis (LC-MS) revealed that the inhibitory effects of each vegetable were associated with the presence of 4-methysulfinylbutyl (sulforaphane) and 7-methylsulphinylheptyl isothiocyanates. Taken together, our data indicate that isothiocyanates derived form broccoli and Rorripa inhibit metalloproteinase 9 activities and also suppress the invasive potential of human MDA-MB-231 breast cancer cells in vitro. The inhibitory effects observed in the current study may contribute to the suppression of carcinogenesis by diets high in cruciferous vegetables

  15. Suppressing epileptic activity in a neural mass model using a closed-loop proportional-integral controller

    Science.gov (United States)

    Wang, Junsong; Niebur, Ernst; Hu, Jinyu; Li, Xiaoli

    2016-01-01

    Closed-loop control is a promising deep brain stimulation (DBS) strategy that could be used to suppress high-amplitude epileptic activity. However, there are currently no analytical approaches to determine the stimulation parameters for effective and safe treatment protocols. Proportional-integral (PI) control is the most extensively used closed-loop control scheme in the field of control engineering because of its simple implementation and perfect performance. In this study, we took Jansen’s neural mass model (NMM) as a test bed to develop a PI-type closed-loop controller for suppressing epileptic activity. A graphical stability analysis method was employed to determine the stabilizing region of the PI controller in the control parameter space, which provided a theoretical guideline for the choice of the PI control parameters. Furthermore, we established the relationship between the parameters of the PI controller and the parameters of the NMM in the form of a stabilizing region, which provided insights into the mechanisms that may suppress epileptic activity in the NMM. The simulation results demonstrated the validity and effectiveness of the proposed closed-loop PI control scheme. PMID:27273563

  16. Aloin Suppresses Lipopolysaccharide-Induced Inflammatory Response and Apoptosis by Inhibiting the Activation of NF-κB

    Directory of Open Access Journals (Sweden)

    Xuan Luo

    2018-02-01

    Full Text Available Numerous herbal-derived natural products are excellent anti-inflammatory agents. Several studies have reported that aloin, the major anthraquinone glycoside obtained from the Aloe species, exhibits anti-inflammatory activity. However, the molecular mechanism of this activity is not well understood. In this report, we found that aloin suppresses lipopolysaccharide-induced pro-inflammatory cytokine secretion and nitric oxide production, and downregulates the expression of tumor necrosis factor alpha (TNF-α, interleukin 6 (IL-6, inducible nitric oxide synthase (iNOS, and cyclooxygenase-2 (COX-2. Aloin inhibits the phosphorylation and acetylation of the NF-κB p65 subunit by suppressing the upstream kinases p38 and Msk1, preventing LPS-induced p65 translocation to the nucleus. We have also shown that aloin inhibits LPS-induced caspase-3 activation and apoptotic cell death. Collectively, these findings suggest that aloin effectively suppresses the inflammatory response, primarily through the inhibition of NF-κB signaling.

  17. Aloin Suppresses Lipopolysaccharide-Induced Inflammatory Response and Apoptosis by Inhibiting the Activation of NF-κB.

    Science.gov (United States)

    Luo, Xuan; Zhang, Haowei; Wei, Xiduan; Shi, Mengjuan; Fan, Ping; Xie, Weidong; Zhang, Yaou; Xu, Naihan

    2018-02-26

    Numerous herbal-derived natural products are excellent anti-inflammatory agents. Several studies have reported that aloin, the major anthraquinone glycoside obtained from the Aloe species, exhibits anti-inflammatory activity. However, the molecular mechanism of this activity is not well understood. In this report, we found that aloin suppresses lipopolysaccharide-induced pro-inflammatory cytokine secretion and nitric oxide production, and downregulates the expression of tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). Aloin inhibits the phosphorylation and acetylation of the NF-κB p65 subunit by suppressing the upstream kinases p38 and Msk1, preventing LPS-induced p65 translocation to the nucleus. We have also shown that aloin inhibits LPS-induced caspase-3 activation and apoptotic cell death. Collectively, these findings suggest that aloin effectively suppresses the inflammatory response, primarily through the inhibition of NF-κB signaling.

  18. Activated MEK Suppresses Activation of PKR and Enables Efficient Replication and In Vivo Oncolysis by Δγ134.5 Mutants of Herpes Simplex Virus 1

    Science.gov (United States)

    Smith, Kerrington D.; Mezhir, James J.; Bickenbach, Kai; Veerapong, Jula; Charron, Jean; Posner, Mitchell C.; Roizman, Bernard; Weichselbaum, Ralph R.

    2006-01-01

    Herpes simplex virus mutants lacking the γ134.5 gene are not destructive to normal tissues but are potent cytolytic agents in human tumor cells in which the activation of double-stranded RNA-dependent protein kinase (PKR) is suppressed. Thus, replication of a Δγ134.5 mutant (R3616) in 12 genetically defined cancer cell lines correlates with suppression of PKR but not with the genotype of RAS. Extensive analyses of two cell lines transduced with either dominant negative MEK (dnMEK) or constitutively active MEK (caMEK) indicated that in R3616 mutant-infected cells dnMEK enabled PKR activation and decreased virus yields, whereas caMEK suppressed PKR and enabled better viral replication and cell destruction in transduced cells in vitro or in mouse xenografts. The results indicate that activated MEK mediates the suppression of PKR and that the status of MEK predicts the ability of Δγ134.5 mutant viruses to replicate in and destroy tumor cells. PMID:16414988

  19. The intact strontium ranelate complex stimulates osteoblastogenesis and suppresses osteoclastogenesis by antagonizing NF-κB activation.

    Science.gov (United States)

    Yamaguchi, Masayoshi; Weitzmann, M Neale

    2012-01-01

    Strontium ranelate, a pharmaceutical agent shown in clinical trials to be effective in managing osteoporosis and reducing fracture risk in postmenopausal women, is relatively unique in its ability to both blunt bone resorption and stimulate bone formation. However, its mechanisms of action are largely unknown. As the nuclear factor-kappa B (NF-κB) activation antagonists both stimulate osteoblastic bone formation and repress osteoclastic bone resorption, we hypothesized that strontium ranelate may achieve its anabolic and anti-catabolic activities by modulating NF-κB activation in bone cells. In this study, osteoclast and osteoblast precursors were treated with intact strontium ranelate or its individual components sodium ranelate and/or strontium chloride, and its effect on in vitro osteoclastogenesis and osteoblastogenesis and on NF-κB activation quantified. Although the activity of strontium ranelate has been attributed to the release of strontium ions, low dose intact strontium ranelate complex, but not sodium ranelate and/or strontium chloride, potently antagonized NF-κB activation in osteoclasts and osteoblasts in vitro, and promoted osteoblast differentiation while suppressing osteoclast formation. Taken together, our data suggest a novel centralized mechanism by which strontium ranelate promotes osteoblast activity and suppresses osteoclastogenesis, based on suppression of NF-κB signal transduction. We further demonstrate that the biological actions of strontium ranelate may be related to low dose of the intact molecule rather than dissociation and release of strontium ions, as previously thought. These data may facilitate the development of additional novel pharmacological agents for the amelioration of osteoporosis, based on NF-κB blockade.

  20. A MAPK-Driven Feedback Loop Suppresses Rac Activity to Promote RhoA-Driven Cancer Cell Invasion.

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    Joseph H R Hetmanski

    2016-05-01

    Full Text Available Cell migration in 3D microenvironments is fundamental to development, homeostasis and the pathobiology of diseases such as cancer. Rab-coupling protein (RCP dependent co-trafficking of α5β1 and EGFR1 promotes cancer cell invasion into fibronectin (FN containing extracellular matrix (ECM, by potentiating EGFR1 signalling at the front of invasive cells. This promotes a switch in RhoGTPase signalling to inhibit Rac1 and activate a RhoA-ROCK-Formin homology domain-containing 3 (FHOD3 pathway and generate filopodial actin-spike protrusions which drive invasion. To further understand the signalling network that drives RCP-driven invasive migration, we generated a Boolean logical model based on existing network pathways/models, where each node can be interrogated by computational simulation. The model predicted an unanticipated feedback loop, whereby Raf/MEK/ERK signalling maintains suppression of Rac1 by inhibiting the Rac-activating Sos1-Eps8-Abi1 complex, allowing RhoA activity to predominate in invasive protrusions. MEK inhibition was sufficient to promote lamellipodia formation and oppose filopodial actin-spike formation, and led to activation of Rac and inactivation of RhoA at the leading edge of cells moving in 3D matrix. Furthermore, MEK inhibition abrogated RCP/α5β1/EGFR1-driven invasive migration. However, upon knockdown of Eps8 (to suppress the Sos1-Abi1-Eps8 complex, MEK inhibition had no effect on RhoGTPase activity and did not oppose invasive migration, suggesting that MEK-ERK signalling suppresses the Rac-activating Sos1-Abi1-Eps8 complex to maintain RhoA activity and promote filopodial actin-spike formation and invasive migration. Our study highlights the predictive potential of mathematical modelling approaches, and demonstrates that a simple intervention (MEK-inhibition could be of therapeutic benefit in preventing invasive migration and metastasis.

  1. Δ9-tetrahydrocannabinol suppresses cytotoxic T lymphocyte function independent of CB1 and CB 2, disrupting early activation events.

    Science.gov (United States)

    Karmaus, Peer W F; Chen, Weimin; Kaplan, Barbara L F; Kaminski, Norbert E

    2012-12-01

    Previously, CD8(+) T cells were found to be a sensitive target for suppression by Δ(9)-tetrahydrocannabinol (Δ(9)-THC) in a murine model of influenza infection. To study the effect of Δ(9)-THC on CD8(+) cytotoxic T lymphocytes (CTL), an allogeneic model of MHC I mismatch was used to elicit CTL. In addition, to determine the requirement for the cannabinoid receptors 1 (CB(1)) and 2 (CB(2)) in Δ(9)-THC-mediated CTL response modulation, mice null for both receptors were used (CB(1) (-/-)CB(2) (-/-)). Δ(9)-THC suppressed CTL function independent of CB(1) and CB(2) as evidenced by reduction of (51)Cr release by CTL generated from CB(1) (-/-)CB(2) (-/-) mice. Furthermore, viability in CD4(+) and CD8(+) cells was reduced in a concentration-dependent manner with Δ(9)-THC, independent of CB(1) and CB(2), but no effect of Δ(9)-THC on proliferation was observed, suggesting that Δ(9)-THC decreases the number of T cells initially activated. Δ(9)-THC increased expression of the activation markers, CD69 in CD8(+) cells and CD25 in CD4(+) cells in a concentration-dependent manner in cells derived from WT and CB(1) (-/-)CB(2) (-/-) mice. Furthermore, Δ(9)-THC synergized with the calcium ionophore, ionomycin, to increase CD69 expression on both CD4(+) and CD8(+) cells. In addition, without stimulation, Δ(9)-THC increased CD69 expression in CD8(+) cells from CB(1) (-/-)CB(2) (-/-) and WT mice. Overall, these results suggest that CB(1) and CB(2) are dispensable for Δ(9)-THC-mediated suppression and that perturbation of Ca(2+) signals during T cell activation plays an important role in the mechanism by which Δ(9)-THC suppresses CTL function.

  2. The effects of long-term dopaminergic treatment on locomotor behavior in rats

    Science.gov (United States)

    Oliveira de Almeida, Welinton Alessandro; Maculano Esteves, Andrea; Leite de Almeida-Júnior, Canuto; Lee, Kil Sun; Kannebley Frank, Miriam; Oliveira Mariano, Melise; Frussa-Filho, Roberto; Tufik, Sergio; Tulio de Mello, Marco

    2014-01-01

    Long-term treatments with dopaminergic agents are associated with adverse effects, including augmentation. Augmentation consists of an exacerbation of restless legs syndrome (a sleep-related movement disorder) symptoms during treatment compared to those experienced during the period before therapy was initiated. The objective of this study was to examine locomotor activity in rats after long-term dopaminergic treatment and its relationship with expression of the D2 receptor, in addition to demonstrating possible evidence of augmentation. The rats were divided into control (CTRL) and drug (Pramipexole—PPX) groups that received daily saline vehicle and PPX treatments, respectively, for 71 days. The locomotor behavior of the animals was evaluated weekly in the Open Field test for 71 days. The expression of the dopamine D2 receptor was evaluated by Western Blot analysis. The animals that received the PPX demonstrated a significant reduction in locomotor activity from day 1 to day 57 and a significant increase in immobility time from day 1 to day 64 relative to baseline values, but these values had returned to baseline levels at 71 days. No changes in the expression of the D2 receptor were demonstrated after treatment with a dopaminergic agonist. This study suggests changes in locomotor activity in rats after long-term PPX treatment that include an immediate reduction of locomotion and an increase in immobilization, and after 64 days, these values returned to baseline levels without evidence of augmentation. In addition, it was not possible to demonstrate a relationship between locomotor activity and the expression of D2 receptors under these conditions. PMID:26483930

  3. The effects of long-term dopaminergic treatment on locomotor behavior in rats

    Directory of Open Access Journals (Sweden)

    Welinton Alessandro Oliveira de Almeida

    2014-12-01

    Full Text Available Long-term treatments with dopaminergic agents are associated with adverse effects, including augmentation. Augmentation consists of an exacerbation of restless legs syndrome (a sleep-related movement disorder symptoms during treatment compared to those experienced during the period before therapy was initiated. The objective of this study was to examine locomotor activity in rats after long-term dopaminergic treatment and its relationship with expression of the D2 receptor, in addition to demonstrating possible evidence of augmentation. The rats were divided into control (CTRL and drug (Pramipexole—PPX groups that received daily saline vehicle and PPX treatments, respectively, for 71 days. The locomotor behavior of the animals was evaluated weekly in the Open Field test for 71 days. The expression of the dopamine D2 receptor was evaluated by Western Blot analysis. The animals that received the PPX demonstrated a significant reduction in locomotor activity from day 1 to day 57 and a significant increase in immobility time from day 1 to day 64 relative to baseline values, but these values had returned to baseline levels at 71 days. No changes in the expression of the D2 receptor were demonstrated after treatment with a dopaminergic agonist. This study suggests changes in locomotor activity in rats after long-term PPX treatment that include an immediate reduction of locomotion and an increase in immobilization, and after 64 days, these values returned to baseline levels without evidence of augmentation. In addition, it was not possible to demonstrate a relationship between locomotor activity and the expression of D2 receptors under these conditions.

  4. Robotic-assisted locomotor training enhances ankle performance in adults with incomplete spinal cord injury.

    Science.gov (United States)

    Krishnan, Vennila; Kindig, Matthew; Mirbagheri, Mehdi

    2016-10-12

    Ankle joint control plays an important role in independent walking. This study investigated the effects of robotic-assisted locomotor training on impaired ankle joint control in individuals with chronic incomplete spinal cord injury. Sixteen individuals with incomplete spinal cord injury underwent 12 one-h sessions of robotic-assisted locomotor training for 4 weeks, while 16 individuals with incomplete spinal cord injury served as inactive controls. Changes in ankle control measures, torque and co-activation were evaluated during maximal voluntary contractions in dorsi- and plantar-flexion. Changes in walking performance measures using Timed Up and Go (TUG), 10-m walk (10MWT) and 6-min walk (6MWT) tests were evaluated at 2 time points: baseline and after 4 weeks. Maximal voluntary contractions torque during both dorsi- and plantar-flexion contractions improved markedly in the robotic-assisted locomotor training group compared with baseline. Furthermore, after the training, co-activation during the dorsi-flexion maximal voluntary contractions decreased in the training group compared with controls. In addition, the training group significantly improved walking mobility (TUG) and speed (10MWT) compared with baseline. Finally, correlation analysis indicated a significant linear relationship between maximal voluntary contraction torques and walking performance measures. These findings provide evidence that robotic-assisted locomotor training improves ankle joint control, which may translate into enhanced walking performance in individuals with chronic incomplete spinal cord injury.

  5. Homocysteine restricts copper availability leading to suppression of cytochrome C oxidase activity in phenylephrine-treated cardiomyocytes.

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    Xiao Zuo

    Full Text Available Cardiomyocyte hypertrophy induced by phenylephrine (PE is accompanied by suppression of cytochrome c oxidase (CCO activity, and copper (Cu supplementation restores CCO activity and reverses the hypertrophy. The present study was aimed to understand the mechanism of PE-induced decrease in CCO activity. Primary cultures of neonatal rat cardiomyocytes were treated with PE at a final concentration of l00 µM in cultures for 72 h to induce cell hypertrophy. The CCO activity was determined by enzymatic assay and changes in CCO subunit COX-IV as well as copper chaperones for CCO (COX17, SCO2, and COX11 were determined by Western blotting. PE treatment increased both intracellular and extracellular homocysteine concentrations and decreased intracellular Cu concentrations. Studies in vitro found that homocysteine and Cu form complexes. Inhibition of the intracellular homocysteine synthesis in the PE-treated cardiomyocytes prevented the increase in the extracellular homocysteine concentration, retained the intracellular Cu concentration, and preserved the CCO activity. PE treatment decreased protein concentrations of the COX-IV, and the Cu chaperones COX17, COX11, and SCO2. These PE effects were prevented by either inhibition of the intracellular homocysteine synthesis or Cu supplementation. Therefore, PE-induced elevation of homocysteine restricts Cu availability through its interaction with Cu and suppression of Cu chaperones, leading to the decrease in CCO enzyme activity.

  6. Consideration of Spillover Effect in Active Vibration Suppression of a Smart Composite Plate Using Piezoelectric Elements

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    Eman Eshraqi

    Full Text Available Abstract In this paper, the problem of vibration suppression of a smart composite plate with bonded piezoelectric patches is considered. A higher order plate model is used for finite element modeling of the plate and the PID controller is used to generate control voltage command to the piezo actuators from the piezo sensors data. Derived formulation and the control algorithm is implemented in a finite element (FE code and the FE modeling results are verified using available results of previous studies. The effect of control gain on the vibration suppression characteristics is studied. Furthermore, since FE modeling reduces the order of the real problem, the problem of un-modeled residual modes on the so-called spillover effect is investigated.

  7. The activity of satellite cells and myonuclei following 8 weeks of strength training in young men with suppressed testosterone levels

    DEFF Research Database (Denmark)

    Kvorning, T; Kadi, F; Schjerling, P.

    2015-01-01

    AIM: To investigate how suppression of endogenous testosterone during an 8-week strength training period influences the activity of satellite cells and myonuclei. METHODS: Twenty-two moderately trained young men participated in this randomized, placebo-controlled, and double-blinded intervention...... study. The participants were randomized to treatment with a GnRH analogue, goserelin (n = 12), which suppresses testosterone or placebo (n = 10) for 12 weeks. The strength training period of 8 weeks started after 4 weeks of treatment and included exercises for all major muscles. Biopsies were obtained......% in placebo and by 52% in goserelin (P changes in satellite cells and myonuclei were seen in type I fibres in either group. Data from the microarray analysis...

  8. Prenylated Flavonoids from Cudrania tricuspidata Suppress Lipopolysaccharide-Induced Neuroinflammatory Activities in BV2 Microglial Cells

    Science.gov (United States)

    Kim, Dong-Cheol; Yoon, Chi-Su; Quang, Tran Hong; Ko, Wonmin; Kim, Jong-Su; Oh, Hyuncheol; Kim, Youn-Chul

    2016-01-01

    In Korea and China, Cudrania tricuspidata Bureau (Moraceae) is an important traditional medicinal plant used to treat lumbago, hemoptysis, and contusions. The C. tricuspidata methanol extract suppressed both production of NO and PGE2 in BV2 microglial cells. Cudraflavanone D (1), isolated from this extract, remarkably suppressed the protein expression of inducible NO synthase and cyclooxygenase-2, and decreased the levels of NO and PGE2 in BV2 microglial cells exposed to lipopolysaccharide. Cudraflavanone D (1) also decreased IL-6, TNF-α, IL-12, and IL-1β production, blocked nuclear translocation of NF-κB heterodimers (p50 and p65) by interrupting the degradation and phosphorylation of inhibitor of IκB-α, and inhibited NF-κB binding. In addition, cudraflavanone D (1) suppressed the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 MAPK pathways. This study indicated that cudraflavanone D (1) can be a potential drug candidate for the cure of neuroinflammation. PMID:26907256

  9. SIRT7 Represses Myc Activity to Suppress ER Stress and Prevent Fatty Liver Disease

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    Jiyung Shin

    2013-11-01

    Full Text Available Nonalcoholic fatty liver disease is the most common chronic liver disorder in developed countries. Its pathogenesis is poorly understood, and therapeutic options are limited. Here, we show that SIRT7, an NAD+-dependent H3K18Ac deacetylase, functions at chromatin to suppress ER stress and prevent the development of fatty liver disease. SIRT7 is induced upon ER stress and is stabilized at the promoters of ribosomal proteins through its interaction with the transcription factor Myc to silence gene expression and to relieve ER stress. SIRT7-deficient mice develop chronic hepatosteatosis resembling human fatty liver disease. Myc inactivation or pharmacological suppression of ER stress alleviates fatty liver caused by SIRT7 deficiency. Importantly, SIRT7 suppresses ER stress and reverts the fatty liver disease in diet-induced obese mice. Our study identifies SIRT7 as a cofactor of Myc for transcriptional repression and delineates a druggable regulatory branch of the ER stress response that prevents and reverts fatty liver disease.

  10. Suppression of NRF2–ARE activity sensitizes chemotherapeutic agent-induced cytotoxicity in human acute monocytic leukemia cells

    International Nuclear Information System (INIS)

    Peng, Hui; Wang, Huihui; Xue, Peng; Hou, Yongyong; Dong, Jian; Zhou, Tong; Qu, Weidong; Peng, Shuangqing; Li, Jin; Carmichael, Paul L.; Nelson, Bud; Clewell, Rebecca; Zhang, Qiang; Andersen, Melvin E.; Pi, Jingbo

    2016-01-01

    Nuclear factor erythroid 2-related factor 2 (NRF2), a master regulator of the antioxidant response element (ARE)-dependent transcription, plays a pivotal role in chemical detoxification in normal and tumor cells. Consistent with previous findings that NRF2–ARE contributes to chemotherapeutic resistance of cancer cells, we found that stable knockdown of NRF2 by lentiviral shRNA in human acute monocytic leukemia (AML) THP-1 cells enhanced the cytotoxicity of several chemotherapeutic agents, including arsenic trioxide (As 2 O 3 ), etoposide and doxorubicin. Using an ARE-luciferase reporter expressed in several human and mouse cells, we identified a set of compounds, including isonicotinic acid amides, isoniazid and ethionamide, that inhibited NRF2–ARE activity. Treatment of THP-1 cells with ethionamide, for instance, significantly reduced mRNA expression of multiple ARE-driven genes under either basal or As 2 O 3 -challenged conditions. As determined by cell viability and cell cycle, suppression of NRF2–ARE by ethionamide also significantly enhanced susceptibility of THP-1 and U937 cells to As 2 O 3 -induced cytotoxicity. In THP-1 cells, the sensitizing effect of ethionamide on As 2 O 3 -induced cytotoxicity was highly dependent on NRF2. To our knowledge, the present study is the first to demonstrate that ethionamide suppresses NRF2–ARE signaling and disrupts the transcriptional network of the antioxidant response in AML cells, leading to sensitization to chemotherapeutic agents. - Highlights: • Identification of novel inhibitors of ARE-dependent transcription • Suppression of NRF2–ARE sensitizes THP-1 cells to chemotherapy. • Ethionamide suppresses ARE-dependent transcriptional activity. • Ethionamide and isoniazid increase the cytotoxicity of As 2 O 3 in AML cells. • Sensitization of THP-1 cells to As 2 O 3 toxicity by ethionamide is NRF2-dependent.

  11. Hotair mediates hepatocarcinogenesis through suppressing miRNA-218 expression and activating P14 and P16 signaling.

    Science.gov (United States)

    Fu, Wei-Ming; Zhu, Xiao; Wang, Wei-Mao; Lu, Ying-Fei; Hu, Bao-Guang; Wang, Hua; Liang, Wei-Cheng; Wang, Shan-Shan; Ko, Chun-Hay; Waye, Mary Miu-Yee; Kung, Hsiang-Fu; Li, Gang; Zhang, Jin-Fang

    2015-10-01

    Long non-coding RNA Hotair has been considered as a pro-oncogene in multiple cancers. Although there is emerging evidence that reveals its biological function and the association with clinical prognosis, the precise mechanism remains largely elusive. We investigated the function and mechanism of Hotair in hepatocellular carcinoma (HCC) cell models and a xenograft mouse model. The regulatory network between miR-218 and Hotair was elucidated by RNA immunoprecipitation and luciferase reporter assays. Finally, the correlation between Hotair, miR-218 and the target gene Bmi-1 were evaluated in 52 paired HCC specimens. In this study, we reported that Hotair negatively regulated miR-218 expression in HCC, which might be mediated through an EZH2-targeting-miR-218-2 promoter regulatory axis. Further investigation revealed that Hotair knockdown dramatically inhibited cell viability and induced G1-phase arrest in vitro and suppressed tumorigenicity in vivo by promoting miR-218 expression. Oncogene Bmi-1 was shown to be a functional target of miR-218, and the main downstream targets signaling, P16(Ink4a) and P14(ARF), were activated in Hotair-suppressed tumorigenesis. In primary human HCC specimens, Hotair and Bmi-1 were concordantly upregulated whereas miR-218 was downregulated in these tissues. Furthermore, Hotair was inversely associated with miR-218 expression and positively correlated with Bmi-1 expression in these clinical tissues. Hotair silence activates P16(Ink4a) and P14(ARF) signaling by enhancing miR-218 expression and suppressing Bmi-1 expression, resulting in the suppression of tumorigenesis in HCC. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  12. A Multiposture Locomotor Training Device with Force-Field Control

    Directory of Open Access Journals (Sweden)

    Jianfeng Sui

    2014-11-01

    Full Text Available This paper introduces a multiposture locomotor training device (MPLTD with a closed-loop control scheme based on joint angle feedback, which is able to overcome various difficulties resulting from mechanical vibration and the weight of trainer to achieve higher accuracy trajectory. By introducing the force-field control scheme used in the closed-loop control, the device can obtain the active-constrained mode including the passive one. The MPLTD is mainly composed of three systems: posture adjusting and weight support system, lower limb exoskeleton system, and control system, of which the lower limb exoskeleton system mainly includes the indifferent equilibrium mechanism with two degrees of freedom (DOF and the driving torque is calculated by the Lagrangian function. In addition, a series of experiments, the weight support and the trajectory accuracy experiment, demonstrate a good performance of mechanical structure and the closed-loop control.

  13. Wogonin Suppresses the Activity of Matrix Metalloproteinase-9 and Inhibits Migration and Invasion in Human Hepatocellular Carcinoma

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    Ming Hong

    2018-02-01

    Full Text Available As one of the major active ingredients in Radix Scutellariae, wogonin has been shown to be associated with various pharmacological activities on cancer cell growth, apoptosis, and cell invasion and migration. Here, we demonstrated that wogonin may harbor potential anti-metastatic activities in hepatocarcinoma (HCC. The anti-metastasis potential of wogonin and its underlying mechanisms were evaluated by ligand–protein docking approach, surface plasmon resonance assay, and in vitro gelatin zymography studies. Our results showed that wogonin (100 μM, 50 μM suppressed MHCC97L and PLC/PRF/5 cells migration and invasion in vitro. The docking approach and surface plasmon resonance assay indicated that the potential binding affinity between wogonin and matrix metalloproteinase-9 (MMP-9 may lead to inhibition of MMP-9 activity and further leads to suppression of tumor metastasis. This conclusion was further verified by Western blot results and gelatin zymography analysis. Wogonin might be a potent treatment option for disrupting the tumor metastasis that favors HCC development. The potential active targets from computational screening integrated with biomedical study may help us to explore the molecular mechanism of herbal medicines.

  14. Iguratimod prevents ovariectomy‑induced bone loss and suppresses osteoclastogenesis via inhibition of peroxisome proliferator‑activated receptor‑γ.

    Science.gov (United States)

    Wu, Ying-Xing; Sun, Yue; Ye, Ya-Ping; Zhang, Peng; Guo, Jia-Chao; Huang, Jun-Ming; Jing, Xing-Zhi; Xiang, Wei; Yu, Shi-Ying; Guo, Feng-Jing

    2017-12-01

    Iguratimod is known for its anti‑inflammatory activities and therapeutic effects in patients with rheumatoid arthritis. It has previously been demonstrated that iguratimod attenuates bone destruction and osteoclast formation in the Walker 256 rat mammary gland carcinoma cell‑induced bone cancer pain model. Therefore, it was hypothesized that iguratimod may additionally exhibit therapeutic effects on benign osteoclast‑associated diseases including postmenopausal osteoporosis. In the present study, ovariectomized mice were used to investigate the effects of iguratimod in vivo. Bone marrow mononuclear cells were cultured to detect the effects of iguratimod on receptor activator of nuclear factor‑κB ligand (RANKL)‑induced osteoclastogenesis in vitro and the molecular mechanisms involved. It was demonstrated that iguratimod may prevent ovariectomy‑induced bone loss by suppressing osteoclast activity in vivo. Consistently, iguratimod may inhibit RANKL‑induced osteoclastogenesis and bone resorption in primary bone marrow mononuclear cells. At the molecular level, peroxisome proliferator‑activated receptor‑γ (PPAR‑γ)/c‑Fos pathway, which is essential in RANKL‑induced osteoclast differentiation, was suppressed by iguratimod. Subsequently, iguratimod decreased the expression of nuclear factor of activated T cells c1 and downstream osteoclast marker genes. The results of the present study demonstrated that iguratimod may inhibit ovariectomy‑induced bone loss and osteoclastogenesis by modulating RANKL signaling. Therefore, iguratimod may act as a novel therapeutic to prevent postmenopausal osteoporosis.

  15. Microglial activation induced by brain trauma is suppressed by post-injury treatment with a PARP inhibitor

    Directory of Open Access Journals (Sweden)

    d'Avila Joana C

    2012-02-01

    Full Text Available Abstract Background Traumatic brain injury (TBI induces activation of microglia. Activated microglia can in turn increase secondary injury and impair recovery. This innate immune response requires hours to days to become fully manifest, thus providing a clinically relevant window of opportunity for therapeutic intervention. Microglial activation is regulated in part by poly(ADP-ribose polymerase-1 (PARP-1. Inhibition of PARP-1 activity suppresses NF-kB-dependent gene transcription and thereby blocks several aspects of microglial activation. Here we evaluated the efficacy of a PARP inhibitor, INO-1001, in suppressing microglial activation after cortical impact in the rat. Methods Rats were subjected to controlled cortical impact and subsequently treated with 10 mg/kg of INO-1001 (or vehicle alone beginning 20 - 24 hours after the TBI. Brains were harvested at several time points for histological evaluation of inflammation and neuronal survival, using markers for microglial activation (morphology and CD11b expression, astrocyte activation (GFAP, and neuronal survival (NeuN. Rats were also evaluated at 8 weeks after TBI using measures of forelimb dexterity: the sticky tape test, cylinder test, and vermicelli test. Results Peak microglial and astrocyte activation was observed 5 to 7 days after this injury. INO-1001 significantly reduced microglial activation in the peri-lesion cortex and ipsilateral hippocampus. No rebound inflammation was observed in rats that were treated with INO-1001 or vehicle for 12 days followed by 4 days without drug. The reduced inflammation was associated with increased neuronal survival in the peri-lesion cortex and improved performance on tests of forelimb dexterity conducted 8 weeks after TBI. Conclusions Treatment with a PARP inhibitor for 12 days after TBI, with the first dose given as long as 20 hours after injury, can reduce inflammation and improve histological and functional outcomes.

  16. Functional organization of locomotor interneurons in the ventral lumbar spinal cord of the newborn rat.

    Directory of Open Access Journals (Sweden)

    Myriam Antri

    Full Text Available Although the mammalian locomotor CPG has been localized to the lumbar spinal cord, the functional-anatomical organization of flexor and extensor interneurons has not been characterized. Here, we tested the hypothesis that flexor and extensor interneuronal networks for walking are physically segregated in the lumbar spinal cord. For this purpose, we performed optical recordings and lesion experiments from a horizontally sectioned lumbar spinal cord isolated from neonate rats. This ventral hemi spinal cord preparation produces well-organized fictive locomotion when superfused with 5-HT/NMDA. The dorsal surface of the preparation was visualized using the Ca(2+ indicator fluo-4 AM, while simultaneously monitoring motor output at ventral roots L2 and L5. Using calcium imaging, we provided a general mapping view of the interneurons that maintained a stable phase relationship with motor output. We showed that the dorsal surface of L1 segment contains a higher density of locomotor rhythmic cells than the other segments. Moreover, L1 segment lesioning induced the most important changes in the locomotor activity in comparison with lesions at the T13 or L2 segments. However, no lesions led to selective disruption of either flexor or extensor output. In addition, this study found no evidence of functional parcellation of locomotor interneurons into flexor and extensor pools at the dorsal-ventral midline of the lumbar spinal cord of the rat.

  17. Activation of glucocorticoid receptors in Müller glia is protective to retinal neurons and suppresses microglial reactivity.

    Science.gov (United States)

    Gallina, Donika; Zelinka, Christopher Paul; Cebulla, Colleen M; Fischer, Andy J

    2015-11-01

    Reactive microglia and macrophages are prevalent in damaged retinas. Glucocorticoid signaling is known to suppress inflammation and the reactivity of microglia and macrophages. In the vertebrate retina, the glucocorticoid receptor (GCR) is known to be activated and localized to the nuclei of Müller glia (Gallina et al., 2014). Accordingly, we investigated how signaling through GCR influences the survival of neurons using the chick retina in vivo as a model system. We applied intraocular injections of GCR agonist or antagonist, assessed microglial reactivity, and the survival of retinal neurons following different damage paradigms. Microglial reactivity was increased in retinas from eyes that were injected with vehicle, and this reactivity was decreased by GCR-agonist dexamethasone (Dex) and increased by GCR-antagonist RU486. We found that activation of GCR suppresses the reactivity of microglia and inhibited the loss of retinal neurons resulting from excitotoxicity. We provide evidence that the protection-promoting effects of Dex were maintained when the microglia were selectively ablated. Similarly, intraocular injections of Dex protected ganglion cells from colchicine-treatment and protected photoreceptors from damage caused by retinal detachment. We conclude that activation of GCR promotes the survival of ganglion cells in colchicine-damaged retinas, promotes the survival of amacrine and bipolar cells in excitotoxin-damaged retinas, and promotes the survival of photoreceptors in detached retinas. We propose that suppression of microglial reactivity is secondary to activation of GCR in Müller glia, and this mode of signaling is an effective means to lessen the damage and vision loss resulting from different types of retinal damage. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Plasma-activated medium suppresses choroidal neovascularization in mice: a new therapeutic concept for age-related macular degeneration.

    Science.gov (United States)

    Ye, Fuxiang; Kaneko, Hiroki; Nagasaka, Yosuke; Ijima, Ryo; Nakamura, Kae; Nagaya, Masatoshi; Takayama, Kei; Kajiyama, Hiroaki; Senga, Takeshi; Tanaka, Hiromasa; Mizuno, Masaaki; Kikkawa, Fumitaka; Hori, Masaru; Terasaki, Hiroko

    2015-01-09

    Choroidal neovascularization (CNV) is the main pathogenesis of age-related macular degeneration (AMD), which leads to severe vision loss in many aged patients in most advanced country. CNV compromises vision via hemorrhage and retinal detachment on account of pathological neovascularization penetrating the retina. Plasma medicine represents the medical application of ionized gas "plasma" that is typically studied in the field of physical science. Here we examined the therapeutic ability of plasma-activated medium (PAM) to suppress CNV. The effect of PAM on vascularization was assessed on the basis of human retinal endothelial cell (HREC) tube formation. In mice, laser photocoagulation was performed to induce CNV (laser-CNV), followed by intravitreal injection of PAM. N-Acetylcysteine was used to examine the role of reactive oxygen species in PAM-induced CNV suppression. Fundus imaging, retinal histology examination, and electroretinography (ERG) were also performed to evaluate PAM-induced retinal toxicity. Interestingly, HREC tube formation and laser-CNV were both reduced by treatment with PAM. N-acetylcysteine only partly neutralized the PAM-induced reduction in laser-CNV. In addition, PAM injection had no effect on regular retinal vessels, nor did it show retinal toxicity in vivo. Our findings indicate the potential of PAM as a novel therapeutic agent for suppressing CNV.

  19. Spermidine Suppresses Age-Associated Memory Impairment by Preventing Adverse Increase of Presynaptic Active Zone Size and Release.

    Directory of Open Access Journals (Sweden)

    Varun K Gupta

    2016-09-01

    Full Text Available Memories are assumed to be formed by sets of synapses changing their structural or functional performance. The efficacy of forming new memories declines with advancing age, but the synaptic changes underlying age-induced memory impairment remain poorly understood. Recently, we found spermidine feeding to specifically suppress age-dependent impairments in forming olfactory memories, providing a mean to search for synaptic changes involved in age-dependent memory impairment. Here, we show that a specific synaptic compartment, the presynaptic active zone (AZ, increases the size of its ultrastructural elaboration and releases significantly more synaptic vesicles with advancing age. These age-induced AZ changes, however, were fully suppressed by spermidine feeding. A genetically enforced enlargement of AZ scaffolds (four gene-copies of BRP impaired memory formation in young animals. Thus, in the Drosophila nervous system, aging AZs seem to steer towards the upper limit of their operational range, limiting synaptic plasticity and contributing to impairment of memory formation. Spermidine feeding suppresses age-dependent memory impairment by counteracting these age-dependent changes directly at the synapse.

  20. Methane Suppresses Microglial Activation Related to Oxidative, Inflammatory, and Apoptotic Injury during Spinal Cord Injury in Rats

    Directory of Open Access Journals (Sweden)

    WeiHeng Wang

    2017-01-01

    Full Text Available Objective. We investigated the hypothesis that methane-rich saline (MS can be used to repair spinal cord injury (SCI in a rat model through suppressing microglial activation related to oxidative, inflammatory, and apoptotic injury. Methods. MS was injected intraperitoneally in rats after SCI. Hematoxylin-eosin (HE staining, oxidative stress, inflammatory parameters, and cell apoptosis were detected 72 h after SCI to determine the optimal dose. Then, we investigated the protective mechanisms and the long-term effects of MS on SCI. HE and microglial activation were observed. Neurological function was evaluated by the Basso, Beattie, and Bresnahan (BBB scale. Results. MS can significantly decrease infarct area and inhibit oxidative stress, inflammation, and cell apoptosis 72 h following SCI. The MS protective effect at a dose of 20 ml/kg was better. Moreover, MS can significantly suppress microglial activation related to oxidative and inflammatory injury after SCI and improve hind limb neurological function. Conclusion. MS could repair SCI and reduce the release of oxidative stress, inflammatory cytokines, and cell apoptosis produced by activated microglia. MS provides a novel and promising strategy for the treatment of SCI.

  1. Inhibition of KDM4A activity as a strategy to suppress interleukin-6 production and attenuate colitis induction.

    Science.gov (United States)

    Ishiguro, Kazuhiro; Watanabe, Osamu; Nakamura, Masanao; Yamamura, Takeshi; Matsushita, Masanobu; Goto, Hidemi; Hirooka, Yoshiki

    2017-07-01

    4-Chloro-7-nitro-2,1,3-benzoxadiazole (NBD-Cl) functions as a hapten and fluoresces upon binding to proteins. Therefore, fluorescence visualization of hapten-proteins is a feature of the colitis induced by NBD-Cl. Using this colitis model, we located activated fibroblasts in the vicinity of hapten-proteins upon colitis induction and observed interleukin (IL)-6 production in the activated fibroblasts. We screened herbal ingredients using primary fibroblasts stimulated with tumor necrosis factor α (TNF-α) and found the suppressive action of Atractylodin on IL-6 production. Under TNF-α stimulation, Atractylodin induced the tri-methylation of histone H3 at lysine residue 9, which impaired the binding between NF-κB and the IL-6 promoter on the genomic DNA. Atractylodin inhibited KDM4A but not KDM6A activity. Atractylodin administration attenuated colitis induction. The KDM4A inhibitor ML324 showed similar actions on IL-6 production and colitis induction. We propose the inhibition of KDM4A activity as a strategy to suppress IL-6 production and attenuate colitis induction. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Morusin induces apoptosis and suppresses NF-κB activity in human colorectal cancer HT-29 cells

    International Nuclear Information System (INIS)

    Lee, J.-C.; Won, S.-J.; Chao, C.-L.; Wu, F.-L.; Liu, H.-S.; Ling Pin; Lin, C.-N.; Su, C.-L.

    2008-01-01

    Morusin is a pure compound isolated from root bark of Morusaustralis (Moraceae). In this study, we demonstrated that morusin significantly inhibited the growth and clonogenicity of human colorectal cancer HT-29 cells. Apoptosis induced by morusin was characterized by accumulation of cells at the sub-G 1 phase, fragmentation of DNA, and condensation of chromatin. Morusin also inhibited the phosphorylation of IKK-α, IKK-β and IκB-α, increased expression of IκB-α, and suppressed nuclear translocation of NF-κB and its DNA binding activity. Dephosphorylation of NF-κB upstream regulators PI3K, Akt and PDK1 was also displayed. In addition, activation of caspase-8, change of mitochondrial membrane potential, release of cytochrome c and Smac/DIABLO, and activation of caspase-9 and -3 were observed at the early time point. Downregulation in the expression of Ku70 and XIAP was exhibited afterward. Caspase-8 or wide-ranging caspase inhibitor suppressed morusin-induced apoptosis. Therefore, the antitumor mechanism of morusin in HT-29 cells may be via activation of caspases and inhibition of NF-κB

  3. Butyrate enhances antibacterial effects while suppressing other features of alternative activation in IL-4-induced macrophages.

    Science.gov (United States)

    Fernando, Maria R; Saxena, Alpana; Reyes, José-Luis; McKay, Derek M

    2016-05-15

    The short-chain fatty acid butyrate is produced by fermentation of dietary fiber by the intestinal microbiota; butyrate is the primary energy source of colonocytes and has immunomodulatory effects. Having shown that macrophages differentiated with IL-4 [M(IL-4)s] can suppress colitis, we hypothesized that butyrate would reinforce an M(IL-4) phenotype. Here, we show that in the presence of butyrate M(IL-4)s display reduced expression of their hallmark markers Arg1 and Ym1 and significantly suppressed LPS-induced nitric oxide, IL-12p40, and IL-10 production. Butyrate treatment likely altered the M(IL-4) phenotype via inhibition of histone deacetylation. Functionally, M(IL-4)s treated with butyrate showed increased phagocytosis and killing of bacteria, compared with M(IL-4) and this was not accompanied by enhanced proinflammatory cytokine production. Culture of regulatory T cells with M(IL-4)s and M(IL-4 + butyrate)s revealed that both macrophage subsets suppressed expression of the regulatory T-cell marker Foxp3. However, Tregs cocultured with M(IL-4 + butyrate) produced less IL-17A than Tregs cocultured with M(IL-4). These data illustrate the importance of butyrate, a microbial-derived metabolite, in the regulation of gut immunity: the demonstration that butyrate promotes phagocytosis in M(IL-4)s that can limit T-cell production of IL-17A reveals novel aspects of bacterial-host interaction in the regulation of intestinal homeostasis. Copyright © 2016 the American Physiological Society.

  4. New approach to the defibrillation problem: Suppression of the spiral wave activity of cardiac tissue

    Science.gov (United States)

    Loskutov, A. Yu.; Vysotskiĭ, S. A.

    2007-01-01

    A model of an excitable medium is considered for describing the development of fibrillation (i.e., spatiotemporal chaos) in cardiac tissue through the generation of a set of coexisting spiral waves. It is shown that a weak external point action on such a medium leads to the suppression of all spiral waves and, correspondingly, to the stabilization of the system dynamics. After reaching the regular regime, only the external source exists in the medium. The frequencies and amplitudes at which such stabilization occurs are determined. The case of the action of several point sources is considered. Analysis is performed using the Bray method to identify the number of spiral waves.

  5. Chimyl Alcohol Suppresses PGE2Synthesis by Human Epidermal Keratinocytes through the Activation of PPAR-γ.

    Science.gov (United States)

    Yokota, Mariko; Yahagi, Shoichi; Tokudome, Yoshihiro; Masaki, Hitoshi

    2018-03-09

    Alkyl glyceryl ethers (AKGs) are widely used as emulsion stabilizers, and their anti-inflammatory effects are well known. Daily exposure to environmental stresses, such as chemicals, low humidity and ultraviolet light (UV), can initiate and promote the development of various skin problems. Among those stresses, it has been established that UV induces skin pigmentation and accelerates premature skin aging due to the inflammation that results. Here, we investigated whether chimyl alcohol (CA), which is an AKG, suppresses the inflammatory process. The suppression of cell damage and the reduction of intracellular levels of reactive oxygen species (ROS) in normal human epidermal keratinocytes (NHEKs) after UVB exposure was evaluated using the Neutral red (NR) and the 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) assays, respectively. Moreover, the expression levels of mRNAs and proteins related to inflammation were evaluated by Realtime RT-PCR and ELISA assays, respectively. CA suppressed prostaglandin E 2 (PGE 2 ) production in UVB-exposed NHEKs according to the down-regulated expression level of cyclooxygenase-2 (COX-2) mRNA. Furthermore, CA up-regulated the mRNA expression levels of peroxisome proliferator-activated receptor (PPAR)-γ, nuclear factor E2-related factor 2 (Nrf2) and γ-glutamyl cysteine synthase (γ-GCS) in NHEKs. Finally, we examined the effects of CA on siPPAR-γtransfected NHEKs. siPPAR-γ transfection of NHEKs abolished the mRNA expression levels of Nrf2 and UVB-stimulated PGE 2 secretion that were regulated by CA. Hence, CA suppresses the UVB-induced COX-2 mRNA expression and PGE 2 production through PPAR-γ as an agonist. We conclude that CA provides useful protection and/or alleviation against UV damage.

  6. Respective roles and interactions of T-lymphocyte and PGE2-mediated monocyte suppressive activities in human newborns and mothers at the time of delivery

    International Nuclear Information System (INIS)

    Durandy, A.; Fischer, A.; Mamas, S.; Dray, F.; Griscelli, C.

    1982-01-01

    Recently the concept of a poorly functional humoral immune response in the newborn was proposed. Data have been presented indicating that the impaired newborn B cell maturation, as shown in vitro in a pokeweed mitogen-induced B cell maturation system, is due both to an immaturity of lymphocyte subsets and to an increased suppressive T activity. In the present work, we present evidence that there exists a predominance of a naturally occurring T lymphocyte suppressive activity in the cord blood in that the removal of the suppressive activity by irradiation allows a normal maturation of newborn B cells. Such normal maturation of newborn B cells can also be obtained using mixed cultures of adult T cells and newborn B cells. Newborn suppressor T cells belong to both EA gamma (+) and EA gamma (-) fractions, and it is not known whether these two groups do or do not belong to different subsets. The PGE2-dependent monocyte suppressive activity does not play any role in the suppression observed in newborns since newborn monocytes are poorly suppressive and since they produce a smaller amount of PGE2 than adult monocytes. Some observations suggest, on the contrary, that the suppressive T lymphocytes can regulate the level of the PGE2-dependent monocyte suppressive activity. It should be noticed that similar observations about T lymphocyte and PGE2-dependent monocyte suppressive activities have been made at the same time using mothers' cells. These observations suggest the possibility that such changes in B cell immune regulation may result from an interaction between maternal and fetal lymphoid cells

  7. The aryl hydrocarbon receptor suppresses osteoblast proliferation and differentiation through the activation of the ERK signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Haitao; Du, Yuxuan; Zhang, Xulong; Sun, Ying; Li, Shentao; Dou, Yunpeng [Department of Immunology, School of Basic Medical Sciences, Capital Medical University, No. 10 Xitoutiao, You An Men, Beijing 100069 (China); Li, Zhanguo [Department of Rheumatology and Immunology, Clinical Immunology Center, Peking University People' s Hospital, No. 11 Xizhimen South Street, Beijing 100044 (China); Yuan, Huihui, E-mail: huihui_yuan@163.com [Department of Immunology, School of Basic Medical Sciences, Capital Medical University, No. 10 Xitoutiao, You An Men, Beijing 100069 (China); Zhao, Wenming, E-mail: zhao-wenming@163.com [Department of Immunology, School of Basic Medical Sciences, Capital Medical University, No. 10 Xitoutiao, You An Men, Beijing 100069 (China)

    2014-11-01

    Ahr activation is known to be associated with synovitis and exacerbated rheumatoid arthritis (RA), but its contributions to bone loss have not been completely elucidated. Osteoblast proliferation and differentiation are abnormal at the erosion site in RA. Here, we reported that the expression of Ahr was increased in the hind paws' bone upon collagen-induced arthritis (CIA) in mice, and the levels of Ahr were negatively correlated with bone mineral density (BMD). In addition, immunofluorescent staining showed that the high expression of Ahr was mainly localized in osteoblasts from the CIA mice compared to normal controls. Moreover, the luciferase intensity of Ahr in the nucleus increased by 12.5% in CIA osteoblasts compared to that in normal controls. In addition, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) activation of the Ahr inhibited pre-osteoblast MC3T3-E1 cellular proliferation and differentiation in a dose-dependent manner. Interestingly, the levels of alkaline phosphatase (ALP) mRNA expression in the osteoblasts of CIA mice were reduced compared to normal controls. In contrast, decreased ALP expression by activated Ahr was completely reversed after pretreatment with an Ahr inhibitor (CH-223191) in MC3T3-E1 cell lines and primary osteoblasts on day 5. Our data further showed that activation of Ahr promoted the phosphorylation of ERK after 5 days. Moreover, Ahr-dependent activation of the ERK signaling pathway decreased the levels of proliferation cells and inhibited ALP activity in MC3T3-E1 cells. These results demonstrated that the high expression of Ahr may suppress osteoblast proliferation and differentiation through activation of the ERK signaling pathway, further enabling bone erosion in CIA mice. - Highlights: • The upregulation of Ahr was localized in osteoblasts of CIA mice. • The overexpression of Ahr suppressed osteoblast development. • The Ahr activated ERK signaling pathway to exacerbate bone erosion.

  8. Naps improve new walkers' locomotor problem solving.

    Science.gov (United States)

    Berger, Sarah E; Scher, Anat

    2017-10-01

    In this first study of the impact of sleep on infants' problem solving of a locomotor task, 28 newly walking infants who were within a week of having given up crawling trained to navigate a shoulder-height tunnel to reach a caregiver waiting at the end. During the transitional window between crawling and walking, infants are reluctant to return to crawling, making this task uniquely challenging. Infants were randomly assigned to either nap or stay awake during a delay between training and a later test session. For the Nap group, efficiency of problem solving improved from training to test, but there was no change for the No Nap group. These findings suggest that for newly walking infants, sleep facilitates learning to solve a novel motor problem. Published by Elsevier Inc.

  9. Fbxw5 suppresses nuclear c-Myb activity via DDB1-Cul4-Rbx1 ligase-mediated sumoylation

    Energy Technology Data Exchange (ETDEWEB)

    Kanei-Ishii, Chie; Nomura, Teruaki; Egoh, Ayako [Laboratory of Molecular Genetics, RIKEN Tsukuba Institute, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074 (Japan); Ishii, Shunsuke, E-mail: sishii@rtc.riken.jp [Laboratory of Molecular Genetics, RIKEN Tsukuba Institute, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074 (Japan)

    2012-09-14

    Highlights: Black-Right-Pointing-Pointer Fbxw5 enhances sumoylation of c-Myb. Black-Right-Pointing-Pointer The DDB1-Cul4A-Rbx1 complex mediates c-Myb sumoylation. Black-Right-Pointing-Pointer The Fbxw5-DDB1-Cul4A-Rdx1 complex is a dual SUMO/ubiquitin ligase. Black-Right-Pointing-Pointer Fbxw5 suppresses the c-Myb trans-activating capacity. -- Abstract: The c-myb proto-oncogene product (c-Myb) is degraded in response to Wnt-1 signaling. In this process, Fbxw7{alpha}, the F-box protein of the SCF complex, binds to c-Myb via its C-terminal WD40 domain, and induces the ubiquitination of c-Myb. Here, we report that Fbxw5, another F-box protein, enhances sumoylation of nuclear c-Myb. Fbxw5 enhanced c-Myb sumoylation via the DDB1-Cul4A-Rbx1 complex. Since the Fbxw5-DDB1-Cul4A-Rbx1 complex was shown to act as a ubiquitin ligase for tumor suppressor TSC2, our results suggest that this complex can function as a dual SUMO/ubiquitin ligase. Fbxw5, which is localized to both nucleus and cytosol, enhanced sumoylation of nuclear c-Myb and induced the localization of c-Myb to nuclear dot-like domains. Co-expression of Fbxw5 suppressed the trans-activation of c-myc promoter by wild-type c-Myb, but not by v-Myb, which lacks the sumoylation sites. These results suggest that multiple E3 ligases suppress c-Myb activity through sumoylation or ubiquitination, and that v-Myb is no longer subject to these negative regulations.

  10. Influence of Brain Stem on Axial and Hindlimb Spinal Locomotor Rhythm Generating Circuits of the Neonatal Mouse

    Directory of Open Access Journals (Sweden)

    Céline Jean-Xavier

    2018-02-01

    Full Text Available The trunk plays a pivotal role in limbed locomotion. Yet, little is known about how the brain stem controls trunk activity during walking. In this study, we assessed the spatiotemporal activity patterns of axial and hindlimb motoneurons (MNs during drug-induced fictive locomotor-like activity (LLA in an isolated brain stem-spinal cord preparation of the neonatal mouse. We also evaluated the extent to which these activity patterns are affected by removal of brain stem. Recordings were made in the segments T7, L2, and L5 using calcium imaging from individual axial MNs in the medial motor column (MMC and hindlimb MNs in lateral motor column (LMC. The MN activities were analyzed during both the rhythmic and the tonic components of LLA, the tonic component being used as a readout of generalized increase in excitability in spinal locomotor networks. The most salient effect of brain stem removal was an increase in locomotor rhythm frequency and a concomitant reduction in burst durations in both MMC and LMC MNs. The lack of effect on the tonic component of LLA indicated specificity of action during the rhythmic component. Cooling-induced silencing of the brain stem reproduced the increase in rhythm frequency and accompanying decrease in burst durations in L2 MMC and LMC, suggesting a dependency on brain stem neuron activity. The work supports the idea that the brain stem locomotor circuits are operational already at birth and further suggests an important role in modulating trunk activity. The brain stem may influence the axial and hindlimb spinal locomotor rhythm generating circuits by extending their range of operation. This may represent a critical step of locomotor development when learning how to walk in different conditions and environments is a major endeavor.

  11. Novel locomotor muscle design in extreme deep-diving whales.

    Science.gov (United States)

    Velten, B P; Dillaman, R M; Kinsey, S T; McLellan, W A; Pabst, D A

    2013-05-15

    Most marine mammals are hypothesized to routinely dive within their aerobic dive limit (ADL). Mammals that regularly perform deep, long-duration dives have locomotor muscles with elevated myoglobin concentrations that are composed of predominantly large, slow-twitch (Type I) fibers with low mitochondrial volume densities (V(mt)). These features contribute to extending ADL by increasing oxygen stores and decreasing metabolic rate. Recent tagging studies, however, have challenged the view that two groups of extreme deep-diving cetaceans dive within their ADLs. Beaked whales (including Ziphius cavirostris and Mesoplodon densirostris) routinely perform the deepest and longest average dives of any air-breathing vertebrate, and short-finned pilot whales (Globicephala macrorhynchus) perform high-speed sprints at depth. We investigated the locomotor muscle morphology and estimated total body oxygen stores of several species within these two groups of cetaceans to determine whether they (1) shared muscle design features with other deep divers and (2) performed dives within their calculated ADLs. Muscle of both cetaceans displayed high myoglobin concentrations and large fibers, as predicted, but novel fiber profiles for diving mammals. Beaked whales possessed a sprinter's fiber-type profile, composed of ~80% fast-twitch (Type II) fibers with low V(mt). Approximately one-third of the muscle fibers of short-finned pilot whales were slow-twitch, oxidative, glycolytic fibers, a rare fiber type for any mammal. The muscle morphology of beaked whales likely decreases the energetic cost of diving, while that of short-finned pilot whales supports high activity events. Calculated ADLs indicate that, at low metabolic rates, both beaked and short-finned pilot whales carry sufficient onboard oxygen to aerobically support their dives.

  12. PROBLEMAS LOCOMOTORES EM FRANGOS DE CORTE - REVISÃO. / LOCOMOTOR PROBLEMS IN BROILER CHICKENS - A REVIEW.

    Directory of Open Access Journals (Sweden)

    IBIARA CORREIA DE LIMA ALMEIDA PAZ

    2008-12-01

    Full Text Available O bem estar animal é, sem dúvida, um dos pontos em que os produtores de aves devem se atentar para conseguir melhor rentabilidade e colocação no mercado externo. No entanto, é necessário ter uma ampla idéia de que alguns pontos impostos por mercados importadores, muitas vezes não tem fundamento científico e tratam-se mais de barreiras não tarifárias que de problemas de produção propriamente ditos. Dentre os vários fatores que afetam o bem estar animal pode-se destacar a incidência de problemas locomotores, principalmente em animais confinados. Estes distúrbios podem acarretar em perdas de até 6% em lotes comercias de frangos de corte, além de outras perdas não mensuráveis em linhas de abate, por fraturas e hematomas. Existem diversas metodologias para diagnosticar problemas locomotores, entretanto, a mais difundida na indústria avícola é o Gait Score, por sua facilidade de aplicação e por englobar os diferentes tipos de problemas locomotores. Sabe-se, contudo que esta metodologia é bastante subjetiva e pode inferir  em  diferentes  níveis  de  avaliação  dependendo  do método  utilizado. Os  problemas locomotores devem ser prevenidos já que depois de estabelecidos as perdas são inevitáveis.

  13. Pyrrolidinium fullerene induces apoptosis by activation of procaspase-9 via suppression of Akt in primary effusion lymphoma

    Energy Technology Data Exchange (ETDEWEB)

    Watanabe, Tadashi [Department of Cell Biology, Kyoto Pharmaceutical University, Misasagi-Shichonocho 1, Yamashinaku, Kyoto 607-8412 (Japan); Nakamura, Shigeo [Department of Chemistry, Nippon Medical School, 1-7-1 Kyonan-cho, Musashino, Tokyo 180-0023 (Japan); Ono, Toshiya; Ui, Sadaharu [Department of Biotechnology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Kofu 400-8511 (Japan); Yagi, Syota; Kagawa, Hiroki [Department of Cell Biology, Kyoto Pharmaceutical University, Misasagi-Shichonocho 1, Yamashinaku, Kyoto 607-8412 (Japan); Watanabe, Hisami [Center of Molecular Biosciences, Tropical Biosphere Research Center, University of the Ryukyus, 1 Senbaru, Nishihara-cho, Okinawa 903-0213 (Japan); Ohe, Tomoyuki; Mashino, Tadahiko [Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512 (Japan); Fujimuro, Masahiro, E-mail: fuji2@mb.kyoto-phu.ac.jp [Department of Cell Biology, Kyoto Pharmaceutical University, Misasagi-Shichonocho 1, Yamashinaku, Kyoto 607-8412 (Japan)

    2014-08-15

    Highlights: • Seven fullerenes were evaluated in terms of their cytotoxic effects on B-lymphomas. • Pyrrolidinium fullerene induced apoptosis of KSHV-infected B-lymphoma PEL cells. • The activation of Akt is essential for PEL cell survival. • Pyrrolidinium fullerene activated caspase-9 by inactivating Akt in PEL cells. • Pyrrolidinium fullerene have potential as novel drugs for the treatment of PEL. - Abstract: Primary effusion lymphoma (PEL) is a subtype of non-Hodgkin’s B-cell lymphoma and is an aggressive neoplasm caused by Kaposi’s sarcoma-associated herpesvirus (KSHV) in immunosuppressed patients. In general, PEL cells are derived from post-germinal center B-cells and are infected with KSHV. To evaluate potential novel anti-tumor compounds against KSHV-associated PEL, seven water-soluble fullerene derivatives were evaluated as potential drug candidates for the treatment of PEL. Herein, we discovered a pyrrolidinium fullerene derivative, 1,1,1′,1′-tetramethyl [60]fullerenodipyrrolidinium diiodide, which induced apoptosis of PEL cells via a novel mechanism, the caspase-9 activation by suppressing the caspase-9 phosphorylation, causing caspase-9 inactivation. Pyrrolidinium fullerene treatment reduced significantly the viability of PEL cells compared with KSHV-uninfected lymphoma cells, and induced the apoptosis of PEL cells by activating caspase-9 via procaspase-9 cleavage. Pyrrolidinium fullerene additionally reduced the Ser473 phosphorylation of Akt and Ser196 of procaspase-9. Ser473-phosphorylated Akt (i.e., activated Akt) phosphorylates Ser196 in procaspase-9, causing inactivation of procaspase-9. We also demonstrated that Akt inhibitors suppressed the proliferation of PEL cells compared with KSHV-uninfected cells. Our data therefore suggest that Akt activation is essential for cell survival in PEL and a pyrrolidinium fullerene derivative induced apoptosis by activating caspase-9 via suppression of Akt in PEL cells. In addition, we evaluated

  14. Curcumin Modulates the Radiosensitivity of Colorectal Cancer Cells by Suppressing Constitutive and Inducible NF-κB Activity

    International Nuclear Information System (INIS)

    Sandur, Santosh K.; Deorukhkar, Amit; Pandey, Manoj K.; Pabon, Ana Maria B.S.; Shentu, Shujun; Guha, Sushovan; Aggarwal, Bharat B.; Krishnan, Sunil

    2009-01-01

    Purpose: Radiation therapy is an integral part of the preoperative treatment of rectal cancers. However, only a minority of patients achieve a complete pathologic response to therapy because of resistance of these tumors to radiation therapy. This resistance may be mediated by constitutively active pro-survival signaling pathways or by inducible/acquired mechanisms in response to radiation therapy. Simultaneous inhibition of these pathways can sensitize these tumors to radiation therapy. Methods and Materials: Human colorectal cancer cells were exposed to clinically relevant doses of gamma rays, and the mechanism of their radioresistance was investigated. We characterized the transcription factor nuclear factor-κB (NF-κB) activation as a mechanism of inducible radioresistance in colorectal cancer and used curcumin, the active ingredient in the yellow spice turmeric, to overcome this resistance. Results: Curcumin inhibited the proliferation and the post-irradiation clonogenic survival of multiple colorectal cancer cell lines. Radiation stimulated NF-κB activity in a dose- and time-dependent manner, whereas curcumin suppressed this radiation-induced NF-κB activation via inhibition of radiation-induced phosphorylation and degradation of inhibitor of κB alpha, inhibition of inhibitor of κB kinase activity, and inhibition of Akt phosphorylation. Curcumin also suppressed NF-κB-regulated gene products (Bcl-2, Bcl-x L , inhibitor of apoptosis protein-2, cyclooxygenase-2, and cyclin D1). Conclusions: Our results suggest that transient inducible NF-κB activation provides a prosurvival response to radiation that may account for development of radioresistance. Curcumin blocks this signaling pathway and potentiates the antitumor effects of radiation therapy.

  15. Ubiquitin carboxyl terminal hydrolase L1 negatively regulates TNFα-mediated vascular smooth muscle cell proliferation via suppressing ERK activation

    International Nuclear Information System (INIS)

    Ichikawa, Tomonaga; Li, Jinqing; Dong, Xiaoyu; Potts, Jay D.; Tang, Dong-Qi; Li, Dong-Sheng; Cui, Taixing

    2010-01-01

    Deubiquitinating enzymes (DUBs) appear to be critical regulators of a multitude of processes such as proliferation, apoptosis, differentiation, and inflammation. We have recently demonstrated that a DUB of ubiquitin carboxyl terminal hydrolase L1 (UCH-L1) inhibits vascular lesion formation via suppressing inflammatory responses in vasculature. However, the precise underlying mechanism remains to be defined. Herein, we report that a posttranscriptional up-regulation of UCH-L1 provides a negative feedback to tumor necrosis factor alpha (TNFα)-mediated activation of extracellular signal-regulated kinases (ERK) and proliferation in vascular smooth muscle cells (VSMCs). In rat adult VSMCs, adenoviral over-expression of UCH-L1 inhibited TNFα-induced activation of ERK and DNA synthesis. In contrast, over-expression of UCH-L1 did not affect platelet derived growth factor (PDGF)-induced VSMC proliferation and activation of growth stimulating cascades including ERK. TNFα hardly altered UCH-L1 mRNA expression and stability; however, up-regulated UCH-L1 protein expression via increasing UCH-L1 translation. These results uncover a novel mechanism by which UCH-L1 suppresses vascular inflammation.

  16. Colchicine therapy in acute coronary syndrome patients acts on caspase-1 to suppress NLRP3 inflammasome monocyte activation.

    Science.gov (United States)

    Robertson, Stacy; Martínez, Gonzalo J; Payet, Cloe A; Barraclough, Jennifer Y; Celermajer, David S; Bursill, Christina; Patel, Sanjay

    2016-07-01

    Inflammasome activation, with subsequent release of pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18, has recently been implicated in atherosclerosis-associated inflammation. This study aims to assess in acute coronary syndrome (ACS) patients (1) inflammasome activation in circulating monocytes and (2) whether short-term oral colchicine, a recognized anti-inflammatory agent that has been shown to be cardio-protective in clinical studies, might acutely suppress inflammasome-dependent inflammation. ACS patients (n=21) were randomized to oral colchicine (1 mg followed by 0.5 mg 1 h later) or no treatment, and compared with untreated healthy controls (n=9). Peripheral venous blood was sampled pre- (day 1) and 24 h post- (day 2) treatment. Monocytes were cultured and stimulated with ATP. Analysis of key inflammasome markers was performed by ELISA. IL-1β secretion increased by 580.4% (PColchicine treatment in ACS patients markedly reduced intracellular and secreted levels of IL-1β compared with pre-treatment levels (Pcolchicine acutely and markedly suppresses monocyte caspase-1 activity, thereby reducing monocyte secretion of IL-1β. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

  17. Cancer/testis antigen PIWIL2 suppresses circadian rhythms by regulating the stability and activity of BMAL1 and CLOCK.

    Science.gov (United States)

    Lu, Yilu; Zheng, Xulei; Hu, Wei; Bian, Shasha; Zhang, Zhiwei; Tao, Dachang; Liu, Yunqiang; Ma, Yongxin

    2017-08-15

    Circadian rhythms are regulated by transcriptional and post-translational feedback loops generated by appropriate functions of clock proteins. Rhythmic degradation of the circadian clock proteins is critical for maintenance of the circadian oscillations. Notably, circadian clock does not work during spermatogenesis and can be disrupted in tumors. However, the underlying mechanism that suppresses circadian rhythms in germ cells and cancer cells remains largely unknown. Here we report that the cancer/testis antigen PIWIL2 can repress circadian rhythms both in the testis and cancer cells. By facilitating SRC binding with PI3K, PIWIL2 activates the PI3K-AKT pathway to phosphorylate and deactivate GSK3β, suppressing GSK3β-induced phosphorylation and degradation of circadian protein BMAL1 and CLOCK. Meanwhile, PIWIL2 can bind with E-Box sequences associated with the BMAL1/CLOCK complex to negatively regulate the transcriptional activation activity of promoters of clock-controlled genes. Taken together, our results first described a function for the germline-specific protein PIWIL2 in regulation of the circadian clock, providing a molecular link between spermatogenesis as well as tumorigenesis to the dysfunction of circadian rhythms.

  18. Proteasome Inhibitor Bortezomib Suppresses Nuclear Factor-Kappa B Activation and Ameliorates Eye Inflammation in Experimental Autoimmune Uveitis

    Directory of Open Access Journals (Sweden)

    Sheng-Min Hsu

    2015-01-01

    Full Text Available Bortezomib is a proteasome inhibitor used for hematologic cancer treatment. Since it can suppress NF-κB activation, which is critical for the inflammatory process, bortezomib has been found to possess anti-inflammatory activity. In this study, we evaluated the effect of bortezomib on experimental autoimmune uveitis (EAU in mice and investigated the potential mechanisms related to NF-κB inactivation. High-dose bortezomib (0.75 mg/kg, low-dose bortezomib (0.15 mg/kg, or phosphate buffered saline was given after EAU induction. We found that the EAU is ameliorated by high-dose bortezomib treatment when compared with low-dose bortezomib or PBS treatment. The DNA-binding activity of NF-κB was suppressed and expression of several key inflammatory mediators including TNF-α, IL-1α, IL-1β, IL-12, IL-17, and MCP-1 was lowered in the high-dose bortezomib-treated group. These results suggest that proteasome inhibition is a promising treatment strategy for autoimmune uveitis.

  19. Suppression of Tumor Growth in Mice by Rationally Designed Pseudopeptide Inhibitors of Fibroblast Activation Protein and Prolyl Oligopeptidase

    Directory of Open Access Journals (Sweden)

    Kenneth W. Jackson

    2015-01-01

    Full Text Available Tumor microenvironments (TMEs are composed of cancer cells, fibroblasts, extracellular matrix, microvessels, and endothelial cells. Two prolyl endopeptidases, fibroblast activation protein (FAP and prolyl oligopeptidase (POP, are commonly overexpressed by epithelial-derived malignancies, with the specificity of FAP expression by cancer stromal fibroblasts suggesting FAP as a possible therapeutic target. Despite overexpression in most cancers and having a role in angiogenesis, inhibition of POP activity has received little attention as an approach to quench tumor growth. We developed two specific and highly effective pseudopeptide inhibitors, M83, which inhibits FAP and POP proteinase activities, and J94, which inhibits only POP. Both suppressed human colon cancer xenograft growth >90% in mice. By immunohistochemical stains, M83- and J94-treated tumors had fewer microvessels, and apoptotic areas were apparent in both. In response to M83, but not J94, disordered collagen accumulations were observed. Neither M83- nor J94-treated mice manifested changes in behavior, weight, or gastrointestinal function. Tumor growth suppression was more extensive than noted with recently reported efforts by others to inhibit FAP proteinase function or reduce FAP expression. Diminished angiogenesis and the accompanying profound reduction in tumor growth suggest that inhibition of either FAP or POP may offer new therapeutic approaches that directly target TMEs.

  20. Kaempferol modulates pro-inflammatory NF-κB activation by suppressing advanced glycation endproducts-induced NADPH oxidase

    Science.gov (United States)

    Kim, Ji Min; Lee, Eun Kyeong; Kim, Dae Hyun; Yu, Byung Pal

    2010-01-01

    Advanced glycation endproducts (AGE) are oxidative products formed from the reaction between carbohydrates and a free amino group of proteins that are provoked by reactive species (RS). It is also known that AGE enhance the generation of RS and that the binding of AGE to a specific AGE receptor (RAGE) induces the activation of the redox-sensitive, pro-inflammatory transcription factor, nuclear factor-kappa B (NF-ĸB). In this current study, we investigated the anti-oxidative effects of short-term kaempferol supplementation on the age-related formation of AGE and the binding activity of RAGE in aged rat kidney. We further investigated the suppressive action of kaempferol against AGE's ability to stimulate activation of pro-inflammatory NF-ĸB and its molecular mechanisms. For this study, we utilized young (6 months old), old (24 months old), and kaempferol-fed (2 and 4 mg/kg/day for 10 days) old rats. In addition, for the molecular work, the rat endothelial cell line, YPEN-1 was used. The results show that AGE and RAGE were increased during aging and that these increases were blunted by kaempferol. In addition, dietary kaempferol reduced age-related increases in NF-κB activity and NF-ĸB-dependant pro-inflammatory gene activity. The most significant new finding from this study is that kaempferol supplementation prevented age-related NF-κB activation by suppressing AGE-induced nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase). Taken together, our results demonstrated that dietary kaempferol exerts its anti-oxidative and anti-inflammatory actions by modulating the age-related NF-κB signaling cascade and its pro-inflammatory genes by suppressing AGE-induced NADPH oxidase activation. Based on these data, dietary kaempferol is proposed as a possible anti-AGE agent that may have the potential for use in anti-inflammation therapies. PMID:20431987

  1. CRFR1 in the ventromedial caudate putamen modulates acute stress-enhanced expression of cocaine locomotor sensitization.

    Science.gov (United States)

    Liu, Shuli; Wang, Zhiyan; Li, Yijing; Sun, Xiaowei; Ge, Feifei; Yang, Mingda; Wang, Xinjuan; Wang, Na; Wang, Junkai; Cui, Cailian

    2017-07-15

    Repeated exposure to psychostimulants induces a long-lasting enhancement of locomotor activity called behavioral sensitization, which is often reinforced by stress after drug withdrawal. The mechanisms underlying these phenomena remain elusive. Here we explored the effects of acute stress 3 or 14 days after the cessation of chronic cocaine treatment on the expression of locomotor sensitization induced by a cocaine challenge in rats and the key brain region and molecular mechanism underlying the phenomenon. A single session of forced swimming, as an acute stress (administered 2 days after the cessation of cocaine), significantly enhanced the expression of cocaine locomotor sensitization 14 days after the final cocaine injection (challenge at 12 days after acute stress) but not 3 days after the cessation of cocaine (challenge at 1 day after acute stress). The result indicated that acute stress enhanced the expression of cocaine locomotor sensitization after incubation for 12 days rather than 1 day after the last cocaine injection. Moreover, the enhancement in locomotor sensitization was paralleled by a selective increase in the number of the c-Fos + cells, the level of CRFR1 mRNA in the ventromedial caudate putamen (vmCPu). Furthermore, the enhancement was significantly attenuated by CRFR1 antagonist NBI-27914 into the vmCPu, implying that the up-regulation of CRFR1 in the vmCPu seems to be critical in the acute stress-enhanced expression of cocaine locomotor sensitization. The findings demonstrate that the long-term effect of acute stress on the expression of cocaine locomotor sensitization is partially mediated by CRFR1 in the vmCPu. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  2. Suppression of neurotoxic lesion-induced seizure activity: evidence for a permanent role for the hippocampus in contextual memory.

    Directory of Open Access Journals (Sweden)

    Fraser T Sparks

    Full Text Available Damage to the hippocampus (HPC using the excitotoxin N-methyl-D-aspartate (NMDA can cause retrograde amnesia for contextual fear memory. This amnesia is typically attributed to loss of cells in the HPC. However, NMDA is also known to cause intense neuronal discharge (seizure activity during the hours that follow its injection. These seizures may have detrimental effects on retrieval of memories. Here we evaluate the possibility that retrograde amnesia is due to NMDA-induced seizure activity or cell damage per se. To assess the effects of NMDA induced activity on contextual memory, we developed a lesion technique that utilizes the neurotoxic effects of NMDA while at the same time suppressing possible associated seizure activity. NMDA and tetrodotoxin (TTX, a sodium channel blocker, are simultaneously infused into the rat HPC, resulting in extensive bilateral damage to the HPC. TTX, co-infused with NMDA, suppresses propagation of seizure activity. Rats received pairings of a novel context with foot shock, after which they received NMDA-induced, TTX+NMDA-induced, or no damage to the HPC at a recent (24 hours or remote (5 weeks time point. After recovery, the rats were placed into the shock context and freezing was scored as an index of fear memory. Rats with an intact HPC exhibited robust memory for the aversive context at both time points, whereas rats that received NMDA or NMDA+TTX lesions showed a significant reduction in learned fear of equal magnitude at both the recent and remote time points. Therefore, it is unlikely that observed retrograde amnesia in contextual fear conditioning are due to disruption of non-HPC networks by propagated seizure activity. Moreover, the memory deficit observed at both time points offers additional evidence supporting the proposition that the HPC has a continuing role in maintaining contextual memories.

  3. Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP.

    Science.gov (United States)

    Liu-Chittenden, Yi; Huang, Bo; Shim, Joong Sup; Chen, Qian; Lee, Se-Jin; Anders, Robert A; Liu, Jun O; Pan, Duojia

    2012-06-15

    The Drosophila TEAD ortholog Scalloped is required for Yki-mediated overgrowth but is largely dispensable for normal tissue growth, suggesting that its mammalian counterpart may be exploited for selective inhibition of oncogenic growth driven by YAP hyperactivation. Here we test this hypothesis genetically and pharmacologically. We show that a dominant-negative TEAD molecule does not perturb normal liver growth but potently suppresses hepatomegaly/tumorigenesis resulting from YAP overexpression or Neurofibromin 2 (NF2)/Merlin inactivation. We further identify verteporfin as a small molecule that inhibits TEAD-YAP association and YAP-induced liver overgrowth. These findings provide proof of principle that inhibiting TEAD-YAP interactions is a pharmacologically viable strategy against the YAP oncoprotein.

  4. Molecular determinants of resistance activation and suppression by Phytophthora infestans effector IPI-O.

    Science.gov (United States)

    Chen, Yu; Liu, Zhenyu; Halterman, Dennis A

    2012-01-01

    Despite intensive breeding efforts, potato late blight, caused by the oomycete pathogen Phytophthora infestans, remains a threat to potato production worldwide because newly evolved pathogen strains have consistently overcome major resistance genes. The potato RB gene, derived from the wild species Solanum bulbocastanum, confers resistance to most P. infestans strains through recognition of members of the pathogen effector family IPI-O. While the majority of IPI-O proteins are recognized by RB to elicit resistance (e.g. IPI-O1, IPI-O2), some family members are able to elude detection (e.g. IPI-O4). In addition, IPI-O4 blocks recognition of IPI-O1, leading to inactivation of RB-mediated programmed cell death. Here, we report results that elucidate molecular mechanisms governing resistance elicitation or suppression of RB by IPI-O. Our data indicate self-association of the RB coiled coil (CC) domain as well as a physical interaction between this domain and the effectors IPI-O4 and IPI-O1. We identified four amino acids within IPI-O that are critical for interaction with the RB CC domain and one of these amino acids, at position 129, determines hypersensitive response (HR) elicitation in planta. IPI-O1 mutant L129P fails to induce HR in presence of RB while IPI-O4 P129L gains the ability to induce an HR. Like IPI-O4, IPI-O1 L129P is also able to suppress the HR mediated by RB, indicating a critical step in the evolution of this gene family. Our results point to a model in which IPI-O effectors can affect RB function through interaction with the RB CC domain.

  5. Antiepileptic activity of total triterpenes isolated from Poria cocos is mediated by suppression of aspartic and glutamic acids in the brain.

    Science.gov (United States)

    Gao, Yanqiong; Yan, Hua; Jin, Ruirui; Lei, Peng

    2016-11-01

    Triterpenes from Poria cocos Wolf (Polyporaceae) have been used to treat various diseases in traditional Chinese medicine. However, the antiepileptic effects and mechanism are not fully understood. The objective of this study is to investigate the antiepileptic properties of total triterpenes (TTP) from the whole P. cocos. The ethanol extract TTP was identified by HPLC fingerprint analysis. Male ICR mice were gavaged (i.g.) with TTP (5, 20, 80 or 160 mg/kg) or reference drugs twice a day for 7 d. Antiepileptic activities of TTP were evaluated by maximal electroshock (MES)- and pentylenetetrazole (PTZ)-induced seizures in mice for 30 and 60 min, respectively. Locomotor activity and Rota-rod tests were performed for 60 min and 5 min, respectively. The levels of glutamic acid (Glu), aspartic acid (Asp), γ-aminobutyric acid (GABA) and glycine (Gly) in convulsive mice were estimated. The chronic epileptic model of Wistar rats was built to measure expressions of glutamate decarboxylase 65 (GAD65) and GABA A in rat brain after TTP treatment. The LC 50 of TTP (i.g.) was above 6 g/kg. TTP (5-160 mg/kg) protected mice against MES- and PTZ-induced convulsions at 65.0% and 62.5%, respectively, but have no effect on rota-rod treadmill; TTP (20-160 mg/kg) significantly reduced the locomotor activities, shortened the onset of pentobarbital sodium-induced sleep; TTP decreased Glu and Asp levels in convulsive mice, but increased the GAD65 and GABA A expressions in chronic epileptic rats at doses usage. TTP extracted from P. cocos possessed potential antiepileptic properties and is a candidate for further antiepileptic drug development.

  6. Ginsenoside Compound K suppresses the hepatic gluconeogenesis via activating adenosine-5'monophosphate kinase: A study in vitro and in vivo.

    Science.gov (United States)

    Wei, Shengnan; Li, Wei; Yu, Yang; Yao, Fan; A, Lixiang; Lan, Xiaoxin; Guan, Fengying; Zhang, Ming; Chen, Li

    2015-10-15

    Compound K (CK) is a final intestinal metabolite of protopanaxadiol-type ginsenoside. We have reported that CK presented anti-diabetic effect via diminishing the expressions of hepatic gluconeogenesis key enzyme. Here, we further explore the possible mechanism of CK on suppression hepatic gluconeogenesis via activation of adenosine-5'monophosphate kinase (AMPK) on type 2 diabetes mice in vivo and in HepG2 cells. Type 2 diabetes mice model was developed by high fat diet combined with STZ injection. 30mg/kg/d CK was orally administrated for 4weeks, the fasting blood glucose level and 2h OGTT were conducted, and the protein expression of AMPK, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), Phosphoenolpyruvate carboxykinase (PEPCK) and Glucose-6-phosphatase (G6Pase) were examined. The mechanism of Compound K on hepatic gluconeogenesis was further explored in HepG2 hepatocytes. Glucose production, the protein expression of AMPK, PEPCK, G6pase and PGC-1α, hepatic nuclear factor 4α (HNF-4α) and forkhead transcription factor O1 (FOXO1) were determined after Compound K treatment at the presence of AMPK inhibitor Compound C. We observed that CK inhibited the expression of PEPCK and G6Pase in the liver and in HepG2 hepatocytes. Meanwhile, CK treatment remarkably increased the activation of AMPK, while decreasing the expressions of PGC-1α, HNF-4α and FOXO1. However, AMPK inhibitor Compound C could reverse these effects of CK on gluconeogenesis in part. The results indicated that the effect of CK on suppression hepatic gluconeogenesis might be via the activation the AMPK activity. Copyright © 2015. Published by Elsevier Inc.

  7. Activation of peroxisome proliferator-activated receptor-{alpha} (PPAR{alpha}) suppresses postprandial lipidemia through fatty acid oxidation in enterocytes

    Energy Technology Data Exchange (ETDEWEB)

    Kimura, Rino [Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011 (Japan); Takahashi, Nobuyuki, E-mail: nobu@kais.kyoto-u.ac.jp [Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011 (Japan); Murota, Kaeko [Department of Life Science, School of Science and Engineering, Kinki University, Osaka 770-8503 (Japan); Yamada, Yuko [Laboratory of Physiological Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011 (Japan); Niiya, Saori; Kanzaki, Noriyuki; Murakami, Yoko [Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011 (Japan); Moriyama, Tatsuya [Department of Applied Cell Biology, Graduate School of Agriculture, Kinki University, Nara 631-8505 (Japan); Goto, Tsuyoshi; Kawada, Teruo [Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011 (Japan)

    2011-06-24

    Highlights: {yields} PPAR{alpha} activation increased mRNA expression levels of fatty acid oxidation-related genes in human intestinal epithelial Caco-2 cells. {yields} PPAR{alpha} activation also increased oxygen consumption rate and CO{sub 2} production and decreased secretion of triglyceride and ApoB from Caco-2 cells. {yields} Orally administration of bezafibrate increased mRNA expression levels of fatty acid oxidation-related genes and CO{sub 2} production in small intestinal epithelial cells. {yields} Treatment with bezafibrate decreased postprandial serum concentration of triglyceride after oral injection of olive oil in mice. {yields} It suggested that intestinal lipid metabolism regulated by PPAR{alpha} activation suppresses postprandial lipidemia. -- Abstract: Activation of peroxisome proliferator-activated receptor (PPAR)-{alpha} which regulates lipid metabolism in peripheral tissues such as the liver and skeletal muscle, decreases circulating lipid levels, thus improving hyperlipidemia under fasting conditions. Recently, postprandial serum lipid levels have been found to correlate more closely to cardiovascular diseases than fasting levels, although fasting hyperlipidemia is considered an important risk of cardiovascular diseases. However, the effect of PPAR{alpha} activation on postprandial lipidemia has not been clarified. In this study, we examined the effects of PPAR{alpha} activation in enterocytes on lipid secretion and postprandial lipidemia. In Caco-2 enterocytes, bezafibrate, a potent PPAR{alpha} agonist, increased mRNA expression levels of fatty acid oxidation-related genes, such as acyl-CoA oxidase, carnitine palmitoyl transferase, and acyl-CoA synthase, and oxygen consumption rate (OCR) and suppressed secretion levels of both triglycerides and apolipoprotein B into the basolateral side. In vivo experiments revealed that feeding high-fat-diet containing bezafibrate increased mRNA expression levels of fatty acid oxidation-related genes and

  8. Different locomotor sensitization responses to repeated cocaine injections are associated with differential phosphorylation of GluA1 in the dorsomedial striatum of adult rats.

    Science.gov (United States)

    Kim, Myonghwan; Kim, Wonju; Baik, Ja-Hyun; Yoon, Bong-June

    2013-11-15

    Behavioral sensitization to psychostimulants reflects neural adaptation, which might share a common mechanism with drug addiction. Outbred male rats show different locomotor sensitization responses to cocaine, and cocaine also produces varied addictive progress in humans. We investigated whether differences in the induction of sensitization would affect the long-term persistence of sensitized locomotor activity, and we sought to determine the molecular basis for the variability in sensitization. Male Sprague-Dawley rats that showed sensitized locomotor responses over 5 consecutive daily cocaine injections (SENS) had significantly lower initial locomotor responses to the 1st cocaine exposure than did rats that did not show locomotor sensitization (NONS). Furthermore, rats that underwent 1 month of cocaine withdrawal after 5 repeated cocaine injections also exhibited sensitized or non-sensitized locomotor responses to a challenge injection of cocaine (SENS-C or NONS-C, respectively). This variability was also related to the initial responsiveness to cocaine. We examined the level of phosphorylation of the GluA1 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropioniate receptor (AMPAR) in the dorsal striatum and found that there were significant differences between the sensitized rats and the non-sensitized rats. pGluA1-Ser831 was increased in the SENS rats during the induction of locomotor sensitization, and pGluA1-Ser845 was increased in the SENS-C rats during the expression of locomotor sensitization. These phosphorylation changes were observed in the dorsomedial striatum (DMS) of adult rats but not in the dorsolateral striatum (DLS) of adults. Our findings suggest that differential phosphorylation of AMPAR might be an important mechanism that contributes to the development of locomotor sensitization to cocaine in adult rats. Copyright © 2013 Elsevier B.V. All rights reserved.

  9. Baicalin and its metabolites suppresses gluconeogenesis through activation of AMPK or AKT in insulin resistant HepG-2 cells.

    Science.gov (United States)

    Wang, Tao; Jiang, Hongmei; Cao, Shijie; Chen, Qian; Cui, Mingyuan; Wang, Zhijie; Li, Dandan; Zhou, Jing; Wang, Tao; Qiu, Feng; Kang, Ning

    2017-12-01

    Scutellaria baicalensis Georgi (S. baicalensis), as a traditional Chinese herbal medicine, is an important component of several famous Chinese medicinal formulas for treating patients with diabetes mellitus. Baicalin (BG), a main bioactive component of S. baicalensis, has been reported to have antidiabetic effects. However, pharmacokinetic studies have indicated that BG has poor oral bioavailability. Therefore, it is hard to explain the pharmacological effects of BG in vivo. Interestingly, several reports show that BG is extensively metabolized in rats and humans. Therefore, we speculate that the BG metabolites might be responsible for the pharmacological effects. In this study, BG and its three metabolites (M1-M3) were examined their effects on glucose consumption in insulin resistant HepG-2 cells with a commercial glucose assay kit. Real-time PCR and western blot assay were used to confirm genes and proteins of interest, respectively. The results demonstrate that BG and its metabolites (except for M3) enhanced the glucose consumption which might be associated with inhibiting the expression of the key gluconeogenic genes, including glucose-6-phosphatase (G6Pase), phosphoenolypyruvate carboxykinase (PEPCK) and glucose transporter 2 (GLUT2). Further study found that BG and M1 could suppress hepatic gluconeogenesis via activation of the AMPK pathway, while M2 could suppress hepatic gluconeogenesis via activation of the PI3K/AKT signaling pathway. Taken together, our findings suggest that both BG and its metabolites have antihyperglycemic activities, and might be the active forms of oral doses of BG in vivo. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  10. Thermal response to firefighting activities in residential structure fires: impact of job assignment and suppression tactic.

    Science.gov (United States)

    Horn, Gavin P; Kesler, Richard M; Kerber, Steve; Fent, Kenneth W; Schroeder, Tad J; Scott, William S; Fehling, Patricia C; Fernhall, Bo; Smith, Denise L

    2018-03-01

    Firefighters' thermal burden is generally attributed to high heat loads from the fire and metabolic heat generation, which may vary between job assignments and suppression tactic employed. Utilising a full-sized residential structure, firefighters were deployed in six job assignments utilising two attack tactics (1. Water applied from the interior, or 2. Exterior water application before transitioning to the interior). Environmental temperatures decreased after water application, but more rapidly with transitional attack. Local ambient temperatures for inside operation firefighters were higher than other positions (average ~10-30 °C). Rapid elevations in skin temperature were found for all job assignments other than outside command. Neck skin temperatures for inside attack firefighters were ~0.5 °C lower when the transitional tactic was employed. Significantly higher core temperatures were measured for the outside ventilation and overhaul positions than the inside positions (~0.6-0.9 °C). Firefighters working at all fireground positions must be monitored and relieved based on intensity and duration. Practitioner Summary: Testing was done to characterise the thermal burden experienced by firefighters in different job assignments who responded to controlled residential fires (with typical furnishings) using two tactics. Ambient, skin and core temperatures varied based on job assignment and tactic employed, with rapid elevations in core temperature in many roles.

  11. Kaempferide Prevents Titanium Particle Induced Osteolysis by Suppressing JNK Activation during Osteoclast Formation.

    Science.gov (United States)

    Jiao, Zixian; Xu, Weifeng; Zheng, Jisi; Shen, Pei; Qin, An; Zhang, Shanyong; Yang, Chi

    2017-11-30

    Kaempferide (KF) is an O-methylated flavonol, a natural plant extract, which is often found in Kaempferia galanga. It has a variety of effects including anti-carcinogenic, anti-inflammatory, anti-oxidant, anti-bacterial and anti-viral properties. In this study, we aimed to investigate whether KF effectively inhibits titanium particle induced calvarial bone loss via down regulation of the JNK signaling pathway. In the mice with titanium particle induced calvarial osteolysis, the Low dose of KF mildly reduced the resorption pits while in the high dose group, fewer scattered pits were observed on the surface of calvarium. Histological examination showed fewer osteoclasts formation in the KF group. In mouse bone marrow macrophages (BMMs) and RAW264.7 cells, KF significantly inhibited the osteoclast formation and bone resorption at 12.5 μM. However, KF does not affect the mature osteoclast F-actin ring formation. But when being co-treated with KF and anisomycin, BMMs differentiated into mature osteoclasts. At the molecular levels, the JNK phosphorylation was inhibited and the osteoclastogenesis-related specific gene expression including V-ATPase d2, TRAP, calcitonin receptor (CTR), c-Fos and NFATc1 was markedly suppressed. In conclusion, these results indicated that KF is a promising agent in the treatment of osteoclast-related diseases.

  12. Evidence for suppression of electroacupuncture on spinal glial activation and behavioral hypersensitivity in a rat model of monoarthritis.

    Science.gov (United States)

    Sun, S; Cao, H; Han, M; Li, T T; Zhao, Z Q; Zhang, Y Q

    2008-01-31

    Our previous study demonstrated that single intrathecal (i.t.) application of fluorocitrate, a glial metabolic inhibitor, synergized electroacupuncture (EA) antagonizing behavioral hypersensitivity in complete Freund's adjuvant (CFA)-induced monoarthritic rat. To further investigate the relationship between spinal glial activation and EA analgesia, the present study examined the effects of multiple EA on spinal glial activation evoked by monoarthritis (MA). The results showed that (1) unilateral intra-articular injection of CFA produced a robust glial activation on the spinal cord, which was associated with the development and maintenance of behavioral hypersensitivity; (2) multiple EA stimulation of ipsilateral "Huantiao" (GB30) and "Yanglingquan" (GB34) acupoints or i.t. injection of fluorocitrate (1 nmol) significantly suppressed spinal glial activation; (3) inhibitory effects of EA on spinal glial activation and behavioral hypersensitivity were significantly enhanced when EA combined with fluorocitrate, indicating that disruption of glial function may potentiate EA analgesia in inflammatory pain states. These data suggested that analgesic effects of EA might be associated with its counter-regulation to spinal glial activation, and thereby provide a potential strategy for the treatment of arthritis.

  13. Reliability review of the remote tool delivery system locomotor

    Energy Technology Data Exchange (ETDEWEB)

    Chesser, J.B.

    1999-04-01

    The locomotor being built by RedZone Robotics is designed to serve as a remote tool delivery (RID) system for waste retrieval, tank cleaning, viewing, and inspection inside the high-level waste tanks 8D-1 and 8D-2 at West Valley Nuclear Services (WVNS). The RTD systm is to be deployed through a tank riser. The locomotor portion of the RTD system is designed to be inserted into the tank and is to be capable of moving around the tank by supporting itself and moving on the tank internal structural columns. The locomotor will serve as a mounting platform for a dexterous manipulator arm. The complete RTD system consists of the locomotor, dexterous manipulator arm, cameras, lights, cables, hoses, cable/hose management system, power supply, and operator control station.

  14. Melatonin acts through MT1/MT2 receptors to activate hypothalamic Akt and suppress hepatic gluconeogenesis in rats.

    Science.gov (United States)

    Faria, Juliana A; Kinote, Andrezza; Ignacio-Souza, Letícia M; de Araújo, Thiago M; Razolli, Daniela S; Doneda, Diego L; Paschoal, Lívia B; Lellis-Santos, Camilo; Bertolini, Gisele L; Velloso, Lício A; Bordin, Silvana; Anhê, Gabriel F

    2013-07-15

    Melatonin can contribute to glucose homeostasis either by decreasing gluconeogenesis or by counteracting insulin resistance in distinct models of obesity. However, the precise mechanism through which melatonin controls glucose homeostasis is not completely understood. Male Wistar rats were administered an intracerebroventricular (icv) injection of melatonin and one of following: an icv injection of a phosphatidylinositol 3-kinase (PI3K) inhibitor, an icv injection of a melatonin receptor (MT) antagonist, or an intraperitoneal (ip) injection of a muscarinic receptor antagonist. Anesthetized rats were subjected to pyruvate tolerance test to estimate in vivo glucose clearance after pyruvate load and in situ liver perfusion to assess hepatic gluconeogenesis. The hypothalamus was removed to determine Akt phosphorylation. Melatonin injections in the central nervous system suppressed hepatic gluconeogenesis and increased hypothalamic Akt phosphorylation. These effects of melatonin were suppressed either by icv injections of PI3K inhibitors and MT antagonists and by ip injection of a muscarinic receptor antagonist. We conclude that melatonin activates hypothalamus-liver communication that may contribute to circadian adjustments of gluconeogenesis. These data further suggest a physiopathological relationship between the circadian disruptions in metabolism and reduced levels of melatonin found in type 2 diabetes patients.

  15. Adenosine A3 Receptor Suppresses Prostate Cancer Metastasis by Inhibiting NADPH Oxidase Activity

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    Sarvesh Jajoo

    2009-11-01

    Full Text Available Prostate cancer is the most commonly diagnosed and second most lethal malignancy in men, due mainly to a lack of effective treatment for the metastatic disease. A number of recent studies have shown that activation of the purine nucleoside receptor, adenosine A3 receptor (A3AR, attenuates proliferation of melanoma, colon, and prostate cancer cells. In the present study, we determined whether activation of the A3AR reduces the ability of prostate cancer cells to migrate in vitro and metastasize in vivo. Using severe combined immunodeficient mice, we show that proliferation and metastasis of AT6.1 rat prostate cancer cells were decreased by the administration of A3AR agonist N6-(3-iodobenzyl adenosine-5′-N-methyluronamide. In vitro studies show that activation of A3AR decreased high basal nicotinamide adenine dinucleotide phosphate (NADPH oxidase activity present in these cells, along with the expression of Rac1 and p47phox subunits of this enzyme. Inhibition of NADPH oxidase activity by the dominant-negative RacN17 or short interfering (siRNA against p47phox reduced both the generation of reactive oxygen species and the invasion of these cells on Matrigel. In addition, we show that membrane association of p47phox and activation of NADPH oxidase is dependent on the activity of the extracellular signal-regulated kinase (ERK1/2 mitogen-activated protein kinase pathway. We also provide evidence that A3AR inhibits ERK1/2 activity in prostate cancer cells through inhibition of adenylyl cyclase and protein kinase A. We conclude that activation of the A3AR in prostate cancer cells reduces protein kinase A-mediated stimulation of ERK1/2, leading to reduced NADPH oxidase activity and cancer cell invasiveness.

  16. VP-16 and alkylating agents activate a common metabolic pathway for suppression of DNA replication

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    Das, S.K.; Berger, N.A.

    1986-05-01

    The cytotoxic effects of etoposide (VP-16) are mediated by topoisomerase II production of protein crosslinked DNA strand breaks. Previous studies have shown that alkylating agent induced DNA damage results in expansion of dTTP pools and reduction of dCTP pools and DNA replication. Studies were conducted with V79 cells to determine whether the metabolic consequences of VP-16 treatment were similar to those induced by alkylating agents. Treatment with 0.5..mu..M VP-16 prolonged the doubling time of V79 cells from 12 to 18 hrs and caused cell volume to increase from 1.1 to 1.6 x 10/sup -12/l. 2mM caffeine completely blocked the volume increase and substantially prevented the prolongation of doubling time. 5..mu..M VP-16 reduced the rate of (/sup 3/H)TdR incorporation by 70%, whereas in the presence of 2mM caffeine, VP-16 caused only a 10% decrease in the rate of (/sup 3/H)TdR incorporation. 4 hr treatment with 5.0..mu..M VP-16 increased dTTP levels from 65 +/- 10 pmol/10/sup 6/ cells to 80 +/- 13 pmol/10/sup 6/ cells and caused dCTP level to decline from 113 +/- 23 pmol/10/sup 6/ cells to 92 +/- 17 pmol/10/sup 6/ cells. These results indicate that the metabolic consequences of VP-16 treatment are similar to alkylating agent treatment and that an increase in dTTP pools with a subsequent effect on ribonucleotide reductase may be a final common pathway by which many cytotoxic agents suppress DNA synthesis.

  17. VP-16 and alkylating agents activate a common metabolic pathway for suppression of DNA replication

    International Nuclear Information System (INIS)

    Das, S.K.; Berger, N.A.

    1986-01-01

    The cytotoxic effects of etoposide (VP-16) are mediated by topoisomerase II production of protein crosslinked DNA strand breaks. Previous studies have shown that alkylating agent induced DNA damage results in expansion of dTTP pools and reduction of dCTP pools and DNA replication. Studies were conducted with V79 cells to determine whether the metabolic consequences of VP-16 treatment were similar to those induced by alkylating agents. Treatment with 0.5μM VP-16 prolonged the doubling time of V79 cells from 12 to 18 hrs and caused cell volume to increase from 1.1 to 1.6 x 10 -12 l. 2mM caffeine completely blocked the volume increase and substantially prevented the prolongation of doubling time. 5μM VP-16 reduced the rate of [ 3 H]TdR incorporation by 70%, whereas in the presence of 2mM caffeine, VP-16 caused only a 10% decrease in the rate of [ 3 H]TdR incorporation. 4 hr treatment with 5.0μM VP-16 increased dTTP levels from 65 +/- 10 pmol/10 6 cells to 80 +/- 13 pmol/10 6 cells and caused dCTP level to decline from 113 +/- 23 pmol/10 6 cells to 92 +/- 17 pmol/10 6 cells. These results indicate that the metabolic consequences of VP-16 treatment are similar to alkylating agent treatment and that an increase in dTTP pools with a subsequent effect on ribonucleotide reductase may be a final common pathway by which many cytotoxic agents suppress DNA synthesis

  18. New perspectives in the renin-angiotensin-aldosterone system (RAAS) II: albumin suppresses angiotensin converting enzyme (ACE) activity in human.

    Science.gov (United States)

    Fagyas, Miklós; Úri, Katalin; Siket, Ivetta M; Fülöp, Gábor Á; Csató, Viktória; Daragó, Andrea; Boczán, Judit; Bányai, Emese; Szentkirályi, István Elek; Maros, Tamás Miklós; Szerafin, Tamás; Édes, István; Papp, Zoltán; Tóth, Attila

    2014-01-01

    About 8% of the adult population is taking angiotensin-converting enzyme (ACE) inhibitors to treat cardiovascular disease including hypertension, myocardial infarction and heart failure. These drugs decrease mortality by up to one-fifth in these patients. We and others have reported previously that endogenous inhibitory substances suppress serum ACE activity, in vivo, similarly to the ACE inhibitor drugs. Here we have made an effort to identify this endogenous ACE inhibitor substance. ACE was crosslinked with interacting proteins in human sera. The crosslinked products were immunoprecipitated and subjected to Western blot. One of the crosslinked products was recognized by both anti-ACE and anti-HSA (human serum albumin) antibodies. Direct ACE-HSA interaction was confirmed by binding assays using purified ACE and HSA. HSA inhibited human purified (circulating) and human recombinant ACE with potencies (IC50) of 5.7 ± 0.7 and 9.5 ± 1.1 mg/mL, respectively. Effects of HSA on the tissue bound native ACE were tested on human saphenous vein samples. Angiotensin I evoked vasoconstriction was inhibited by HSA in this vascular tissue (maximal force with HSA: 6.14 ± 1.34 mN, without HSA: 13.54 ± 2.63 mN), while HSA was without effects on angiotensin II mediated constrictions (maximal force with HSA: 18.73 ± 2.17 mN, without HSA: 19.22 ± 3.50 mN). The main finding of this study is that HSA was identified as a potent physiological inhibitor of the ACE. The enzymatic activity of ACE appears to be almost completely suppressed by HSA when it is present in its physiological concentration. These data suggest that angiotensin I conversion is limited by low physiological ACE activities, in vivo.

  19. Curcumin suppresses the production of interleukin-6 in Prevotella intermedia lipopolysaccharide-activated RAW 264.7 cells.

    Science.gov (United States)

    Kim, Sung-Jo

    2011-06-01

    Curcumin is known to exert numerous biological effects including anti-inflammatory activity. In this study, we investigated the effects of curcumin on the production of interleukin-6 (IL-6) by murine macrophage-like RAW 264.7 cells stimulated with lipopolysaccharide (LPS) from Prevotella intermedia, a major cause of inflammatory periodontal disease, and sought to determine the underlying mechanisms of action. LPS was prepared from lyophilized P. intermedia ATCC 25611 cells by the standard hot phenol-water method. Culture supernatants were collected and assayed for IL-6. We used real-time polymerase chain reaction to detect IL-6 mRNA expression. IκB-α degradation, nuclear translocation of NF-κB subunits, and STAT1 phosphorylation were characterized via immunoblotting. DNA-binding of NF-κB was also analyzed. Curcumin strongly suppressed the production of IL-6 at both gene transcription and translation levels in P. intermedia LPS-activated RAW 264.7 cells. Curcumin did not inhibit the degradation of IκB-α induced by P. intermedia LPS. Curcumin blocked NF-κB signaling through the inhibition of nuclear translocation of NF-κB p50 subunit. Curcumin also attenuated DNA binding activity of p50 and p65 subunits and suppressed STAT1 phosphorylation. Although further study is required to explore the detailed mechanism of action, curcumin may contribute to blockade of the host-destructive processes mediated by IL-6 and appears to have potential therapeutic values in the treatment of inflammatory periodontal disease.

  20. Cross-activating invariant NKT cells and kupffer cells suppress cholestatic liver injury in a mouse model of biliary obstruction.

    Directory of Open Access Journals (Sweden)

    Caroline C Duwaerts

    Full Text Available Both Kupffer cells and invariant natural killer T (iNKT cells suppress neutrophil-dependent liver injury in a mouse model of biliary obstruction. We hypothesize that these roles are interdependent and require iNKT cell-Kupffer cell cross-activation. Female, wild-type and iNKT cell-deficient C57Bl/6 mice were injected with magnetic beads 3 days prior to bile duct ligation (BDL in order to facilitate subsequent Kupffer cell isolation. On day three post-BDL, the animals were euthanized and the livers dissected. Necrosis was scored; Kupffer cells were isolated and cell surface marker expression (flow cytometry, mRNA expression (qtPCR, nitric oxide (NO (. production (Griess reaction, and protein secretion (cytometric bead-array or ELISAs were determined. To address the potential role of NO (. in suppressing neutrophil accumulation, a group of WT mice received 1400W, a specific inducible nitric oxide synthase (iNOS inhibitor, prior to BDL. To clarify the mechanisms underlying Kupffer cell-iNKT cell cross-activation, WT animals were administered anti-IFN-γ or anti-lymphocyte function-associated antigen (LFA-1 antibody prior to BDL. Compared to their WT counterparts, Kupffer cells obtained from BDL iNKT cell-deficient mice expressed lower iNOS mRNA levels, produced less NO (. , and secreted more neutrophil chemoattractants. Both iNOS inhibition and IFN-γ neutralization increased neutrophil accumulation in the livers of BDL WT mice. Anti-LFA-1 pre-treatment reduced iNKT cell accumulation in these same animals. These data indicate that the LFA-1-dependent cross-activation of iNKT cells and Kupffer cells inhibits neutrophil accumulation and cholestatic liver injury.